Chronic Antigenic Stimulation Research Articles

Targeting mitochondrial quality control of T cells: Regulating the immune response in HCC.

Most of the primary hepatocellular carcinoma (HCC) develops from Viral Hepatitis including Hepatitis B virus, Hepatitis C Virus, and Nonalcoholic Steatohepatitis. Herein, T cells play crucial roles combined with chronic inflammation and chronic viral infection. However, T cells are gradually exhausted under chronic antigenic stimulation, which leads to T cell exhaustion in the tumor microenvironment, and the exhaustion is associated with mitochondrial dysfunction in T cells. Meanwhile, mitochondria play a crucial role in altering T cells’ metabolism modes to achieve desirable immunological responses, wherein mitochondria maintain quality control (MQC) and promote metabolism regulation in the microenvironment. Although immune checkpoint inhibitors have been widely used in clinical practice, there are some limitations in the therapeutic effect, thus combining immune checkpoint inhibitors with targeting mitochondrial biogenesis may enhance cellular metabolic adaptation and reverse the exhausted state. At present, several studies on mitochondrial quality control in HCC have been reported, however, there are gaps in the regulation of immune cell function by mitochondrial metabolism, particularly the modulating of T cell immune function. Hence, this review summarizes and discusses existing studies on the effects of MQC on T cell populations in liver diseases induced by HCC, it would be clued by mitochondrial quality control events.

Antibody-mediated allograft rejection is associated with an increase in peripheral differentiated CD28-CD8+ T cells - Analyses of a cohort of 1032 kidney transplant recipients.

SummaryBackgroundCD28-CD8+ T cells represent a differentiated CD8+ T cell subset that is found to be increased in various conditions associated with chronic antigenic stimulation such as aging, chronic viral infections, autoimmune diseases, cancers, and allotransplantation.MethodsUsing multivariate models, we analyzed a large cohort of 1032 kidney transplant patients in whom 1495 kidney graft biopsies were performed concomitant with a peripheral blood leukocyte phenotyping by flow cytometry. We investigated the association between the level of CD28-CD8+ T cells in the blood and the diagnosis of graft rejection according to the recent Banff classification of renal allograft pathology.FindingsWe found that antibody-mediated rejection (ABMR) was associated with a significant increase in the percentage as well as the absolute number of CD28-CD8+ T cells in the peripheral blood of kidney transplant patients at the time of biopsy. The confounder-adjusted mean difference of log percentage and log absolute value between the ABMR group and the normal/subnormal histology group were 0.29 (p=0.0004) and 0.38 (p=0.0004), respectively. Moreover, we showed that CD28-CD8+ T cells from the patients diagnosed with ABMR responded more rigorously to TCR and FcγRIIIA (CD16) engagement compared to their CD28+ counterparts as evidenced by an increase in the expression of IFNγ, TNFα, and CD107a.InterpretationCollectively, our data suggest that differentiated CD28-CD8+ T cells, with increased frequency, number, and function, may participate in the pathobiology of ABMR. Further studies are warranted to clarify the immunological role of this T cell subset in kidney graft rejection.FundingAgence nationale de la recherche (France).

109 Mutations in the T-cell receptor antigen-binding region of malignant cells in mycosis fungoides coincide with clinical and histological progression

Chronic T-cell antigen stimulation has long been suggested to contribute to carcinogenesis in mycosis fungoides (MF), but evidence of this phenomenon is lacking at the genetic level. Furthermore, mutations that alter malignant T-cells’ antigen specificities have not been previously described in MF. Here, we report evidence from two patients whereby the presence of single base substitutions (SBS) in the antigen-binding regions of the malignant clones’ T-cell receptors (TCR) coincide with changes in clinical behavior.

Comorbidities associated with mycosis fungoides: A case-control study in the All of Us database

To the Editor: Mycosis fungoides (MF) is the most prevalent form of cutaneous T-cell lymphoma and is considered to be a disease of chronic antigen stimulation.1 Single-center studies have shown MF to be significantly associated with autoimmune illness, cardiovascular comorbidities, and T-cell-mediated dermatologic disease,2 yet these findings remain to be validated in a nationwide cohort of American patients. Here, we evaluate comorbidities associated with MF using the All of Us database, a recently launched initiative by the National Institutes of Health that aims to provide health data on over 1 million Americans, seeking to include groups that have been historically underrepresented in research.

Abstract 3613: CD28 signaling controls maintenance and differentiation of PD1+CD8 T cells during chronic antigen stimulation

Abstract During chronic infections and cancer, CD8 T cells that recognize pathogens/tumors can persist in a dysfunctional state characterized by high expression of the inhibitory receptor Programmed Cell Death (PD)-1. PD-1+ CD8 T cells are heterogeneous: T cell factor (TCF)-1+PD-1+ progenitor exhausted cells (Tpex) are capable of self-renewal and give rise to the more differentiated subpopulation of TCF-1negPD-1+ CD8 T cells that can retain some effector-like function. Tpex are essential for the maintenance of the antigen-specific T cell pool during chronic stimulation, and in animal models, only these cells respond to PD-1 blockade. In cancer patients, the presence of Tpex cells in tumors has been associated with response to PD-1 targeted therapy. However, it has been reported that the presence of these cells in the tumor microenvironment requires a specific niche, and the molecular mechanisms supporting maintenance of Tpex remains to be investigated. Tpex have high CD28 expression, and we have shown that during PD-1 targeted therapies, CD28 costimulation is required for the reinvigoration of CD8 T cell responses. In this study, we sought to understand the role of sustained CD28 signaling for self-renewal and differentiation of Tpex cells. In mice chronically infected with lymphocytic choriomeningitis virus (LCMV), we abrogated CD28 signaling by blockade of anti-B7-1/B7-2, and observed a sharp reduction of virus-specific CD8 T cells (both TCF-1+ and TCF-1neg subsets). By contrast, B7-2 single blockade resulted in reduction of differentiated TCF-1neg virus-specific cells, yet the Tpex subset was not affected. We hypothesized that stronger CD28 signaling might be required for differentiation of Tpex cells into TCF-1neg, whereas weaker CD28 signaling would be sufficient for Tpex self-renewal. To address this question, we performed conditional deletion of Cd28 on PD-1+ CD8 T cells in mice with established chronic infection. Deletion of both Cd28 alleles resulted in reduction of TCF-1+ and TCF-1neg subsets. In contrast, when CD28 signaling was reduced (deletion of one allele), TCF-1neg PD-1+ CD8 T cells were decreased but the number of Tpex cells was not affected. We performed RNA sequencing and metabolic assays to better understand the role of CD28 signaling on PD-1+ CD8 T cells. These data revealed that sustained CD28 signaling during persistent antigen stimulation is required to maintain mitochondrial fitness. Our work support the novel hypothesis that CD28 signaling strength modulates cell fate decision of Tpex cells through metabolic regulation. Our data also suggest that antigen presenting cells capable of providing ligands to CD28 are required for the long-term maintenance of antigen-specific T cells during chronic stimulation. These findings provide key insights about PD-1+ CD8 T cells, with important implications for checkpoint therapy in cancer, including longevity of responses. Citation Format: Etienne Humblin, Verena Van der Heide, Dan Filipescu, Ashley Lu, Alessandra Soares-Schanoski, Myvizhi Selvan, Laila Horta, Zeynep Gumus, Emily Bernstein, Jerry Chipuk, Dirk Homann, Alice O. Kamphorst. CD28 signaling controls maintenance and differentiation of PD1+CD8 T cells during chronic antigen stimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3613.

Abstract 3602: Mechanisms of CAR T cell dysfunction and identification of transcription factors that drive the exhaustion phenotype

Abstract Chimeric antigen receptor (CAR) T cell immunotherapy is FDA approved for the treatment of a subset of B cell malignancies but has shown limited clinical success in solid tumor therapy. T cell exhaustion is an important factor involved in treatment failure, and can, in part, result from continuous stimulation of the CAR by tumor cells expressing the cognate antigen. To gain deeper understanding of CAR T cell exhaustion induced by chronic antigen exposure (CAE), we developed and validated a robust in vitro model, in which mesothelin-redirected CAR T cells (M5CAR) were continuously stimulated with mesothelin-expressing AsPC-1 pancreatic tumor cells such that tumor cells were never cleared, and we characterized these CAE CAR T cells by gene expression at population and single-cell levels, and by epigenetic analyses. CAE M5CAR T cells recapitulate the hallmarks of T cell exhaustion, including reduced proliferation, down-modulation of surface CAR, decreased cytokine production, and reduced cytotoxicity. In addition, CAR T cells undergoing CAE have a transcriptional signature and an epigenetic landscape consistent with exhaustion. Further, transcriptomic analysis revealed that CAE M5CAR T cells undergo a transition from T cells to a post-thymic NK-like T cell phenotype. This plasticity was confirmed by TCR lineage tracing and was also detected in CD19 CAR T cells analyzed from post-infusion blood from DLBCL patients and in M5CAR T cells infiltrating relapsed tumors derived from a xenograft NSG/AsPC-1 mouse model. The dysfunctional signature and the NK phenotype were further detected in vivo by transcriptomic analysis in Ly95 TCR-specific TILs infiltrating NY-ESO-1 tumors. Among the genes included in the dysfunctional signature, the transcription factors SOX4 and ID3 were identified as potential regulators of dysfunction by differential gene expression and pathway analyses. To determine their role in the establishment of a dysfunctional phenotype, we generated ID3KO.M5 and SOX4KO.M5 CAR T cells using CRISPR technology in primary human lymphocytes. The cytotoxic potential of the M5 CAR T cell product generated was not modified by the genetic disruption of the transcription factors. However, when CAR T cells were challenged with chronic antigen stimulation, KO CAR T cells showed a significant reduction of the dysfunctional signature and the NK-like T cell gene expression. Importantly, CAE KO CAR T cells exhibit improved cytotoxicity as compared to Mock.M5CAR T cells. In summary, we have developed a robust in vitro model that recapitulates the hallmarks of T cell exhaustion and that facilitated the identification of a gene signature defining CAR dysregulation, a T-to-NK-like-T cell transition as a novel feature of CAR T cell dysfunction and the transcription factors SOX4 and ID3 as key regulators of CAR T cell exhaustion. Citation Format: M. Angela Aznar, Charly R. Good, Shunichiro Kuramitsu, Parisa Samareh, Sangya Agarwal, Greg Donahue, Kenichi Ishiyama, Nils Wellhausen, Austin K. Rennels, Yujie Ma, Lifeng Tian, Sonia Guedan, Katherine A. Alexander, Zhen Zhang, Philipp C. Rommel, Nathan Singh, Karl M. Glastad, Max W. Richardson, Keisuke Watanabe, Janos L. Tanyi, Mark H. O’Hara, Marco Ruella, Simon F. Lacey, Edmund K. Moon, Stephen J. Schuster, Steven M. Albelda, Lewis L. Lanier, Regina M. Young, Shelley L. Berger, Carl H. June. Mechanisms of CAR T cell dysfunction and identification of transcription factors that drive the exhaustion phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3602.

Abstract 4239: Development of multi-targeting immunomodulatory SeekR RNA therapeutics to overcome resistance to PD-1 blockade

Abstract T-cell exhaustion describes the dysfunctional state of effector T cells in the tumor microenvironment that results from chronic and prolonged exposure to antigen. It also represents an important mechanism of clinical resistance to immune checkpoint blockade. Recently, the transcription factor NR4A1 has been shown to be upregulated in tumor-specific T cells and plays a role in driving exhaustion during chronic antigen stimulation of T cells. Pro-oncogenic activities of NR4A1 have long been observed in various solid tumors including colorectal and breast cancers, and co-expression of NR4A1 with known immune checkpoint markers such as PD-L1 have also been observed in various cancer cell lines. These findings have identified NR4A1 as an important target for overcoming resistance to cancer immunotherapy. We hypothesize that multi-targeting to simultaneously block PD-1 signaling and silence NR4A1 gene expression can reverse T-cell exhaustion and expand the clinical benefit of PD-1 blockade in immune therapy resistant solid tumors. Using our SeekR™ RNA therapeutics platform, we combined aptamer binders to PD-1 with siRNA against NR4A1, andNR4A1 and evaluated their ability to reverse T-cell exhaustion and re-activate T-cell based anticancer immunity in solid tumors. Specifically, we created SeekR™ therapeutic RNA molecules with dual flanking RNA aptamers binders to PD-1 and other checkpoint inhibitors, connected by a double stranded bridge that encodes for siRNA silencers that target multiple immunomodulatory genes, such as NR4A1. The novel anti-PD-1 RNA aptamer component serve to: A) direct and deliver the SeekR™ RNA oligo therapeutics to exhausted T-cells that express PD-1 receptors; and B) internalize the siRNA component into the T-cells. The siRNA components of the SeekR™ serve to silence NR4A1 which lead to reversal of the cytotoxic T-cell exhausted phenotype following chronic in-vitro stimulation. These results demonstrate that dual targeting of PD-1 and NR4A1 has the potential to reverse T-cell exhaustion and the potential to overcome cancer immunotherapy resistance in the clinic. Citation Format: Marvin O'ketch, Victoria A. Love, Jeffrey A. Kiefer, David W. Lee, Lizette A. Castaño, Spyro Mousses, David O. Azorsa. Development of multi-targeting immunomodulatory SeekR RNA therapeutics to overcome resistance to PD-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4239.

Pathogenesis and Treatment of T-Large Granular Lymphocytic Leukemia (T-LGLL) in the Setting of Rheumatic Disease.

A complex relationship exists between rheumatic diseases and cancer. This delicate balance between chronic inflammation and malignant cell transformation in hematologic neoplasms has been observed, but is not well defined. Large Granular Lymphocyte (LGL) leukemia is at the intersection of a clonal lymphoproliferative disease, chronic inflammation, and autoimmunity. The association between rheumatoid arthritis (RA) and the spectrum of Felty’s Syndrome is well-known. Other rheumatic disorders have been reported including systemic lupus erythematosus (SLE), Sjogren’s Syndrome (SS), vasculitis, Behcet’s Disease (BD) and systemic sclerosis. The association between T-LGLL and rheumatic disease pathogenesis has been hypothesized, but has not yet been fully understood. Components of a shared pathogenesis includes chronic antigen stimulation, JAK-STAT pathway activation and overlap of various cytokines. We will summarize current knowledge on the molecular understanding between T-LGLL and rheumatic disease. There are many potential areas of research to help meet this need and lead to development of targeted therapeutic options.

BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4+ T cell responses to persistent antigen

Soon after activation, CD4+ Tcells are segregated into BCL6+ follicular helper (Tfh) and BCL6- effector (Teff) Tcells. Here, we explored how these subsets are maintained during chronic antigen stimulation using the mouse chronic LCMV infection model. Using single cell-transcriptomic and epigenomic analyses, we identified a population of PD-1+ TCF-1+ CD4+ Tcells with memory-like features. TCR clonal tracing and adoptive transfer experiments demonstrated that these cells have self-renewal capacity and continue to give rise to both Teff and Tfh cells, thus functioning as progenitor cells. Conditional deletion experiments showed Bcl6-dependent development of these progenitors, which were essential for sustaining antigen-specific CD4+ Tcell responses to chronic infection. An analogous CD4+ Tcell population developed in draining lymph nodes in response to tumors. Our study reveals the heterogeneity and plasticity of CD4+ Tcells during persistent antigen exposure and highlights their population dynamics through a stable, bipotent intermediate state.

Epigenetic regulation of T cell exhaustion.

Chronic antigen stimulation during viral infections and cancer can lead to T cell exhaustion, which is characterized by reduced effector function and proliferation, and the expression of inhibitory immune checkpoint receptors. Recent studies have demonstrated that T cell exhaustion results in wholescale epigenetic remodeling that confers phenotypic stability to these cells and prevents T cell reinvigoration by checkpoint blockade. Here, we review foundational technologies to profile the epigenome at multiple scales, including mapping the locations of transcription factors and histone modifications, DNA methylation and three-dimensional genome conformation. We discuss how these technologies have elucidated the development and epigenetic regulation of exhausted T cells and functional implications across viral infection, cancer, autoimmunity and engineered T cell therapies. Finally, we cover emerging multi-omic and genome engineering technologies, current and upcoming opportunities to apply these to T cell exhaustion, and therapeutic opportunities for T cell engineering in the clinic.

Transgenic Expression of IL15 Retains CD123-Redirected T Cells in a Less Differentiated State Resulting in Improved Anti-AML Activity in Autologous AML PDX Models.

Immunotherapy with T-cells expressing bispecific T-cell engagers (ENG T-cells) is a promising approach to improve the outcomes for patients with recurrent/refractory acute myeloid leukemia (AML). However, similar to T-cells expressing chimeric antigen receptors (CARs), their antitumor activity is limited in the setting of chronic antigen stimulation. We therefore set out to explore whether transgenic expression of IL15 improves the effector function of ENG T-cells targeting CD123-positive AML. T-cells expressing CD123-specific ENG (CD123-ENG) ± IL15 were generated by retroviral transduction from peripheral blood T cells from healthy donors or patients with AML. In this study, we characterized in detail the phenotype and effector functions of ENG T-cell populations in vitro and in vivo. IL15-expressing CD123-ENG (CD123-ENG.IL15) T-cells retained their antigen-specificity and effector function in the setting of chronic antigen exposure for more 30 days of coculture with AML blasts in contrast to CD123-ENG T-cells, whose effector function rapidly eroded. Furthermore, CD123-ENG.IL15 T-cells remained in a less differentiated state as judged by a high frequency of naïve/memory stem T-cell-like cells (CD45RA+CCR7+/CD45RO−CD62L+ cells) without evidence of T-cell exhaustion. Single cell cytokine profiling using IsoPlexis revealed enhanced T-cell polyfunctionality of CD123-ENG.IL15 T-cells as judged by effector cytokine production, including, granzyme B, IFN-γ, MIP-1α, perforin, TNF-α, and TNF-β. In vivo, CD123-ENG.IL15 T-cells exhibited superior antigen-specific anti-AML activity and T-cell persistence in both peripheral blood and tissues (BM, spleens, and livers), resulting in a significant survival advantage in one AML xenograft model and two autologous AML PDX models. In conclusion, we demonstrate here that the expansion, persistence, and anti-AML activity of CD123-ENG T-cells can be significantly improved by transgenic expression of IL15, which promotes a naïve/TSCM-like phenotype. However, we also highlight that targeting a single tumor antigen (CD123) can lead to immune escape, reinforcing the need to develop approaches to target multiple antigens. Likewise, our study demonstrates that it is feasible to evaluate autologous T cells in AML PDX models, which will be critical for future preclinical evaluations of next generation AML-redirected T-cell therapies.

Association of Flame-Retardant Clothing With Mycosis Fungoides: A Retrospective Analysis.

IntroductionMycosis fungoides (MF), the most prevalent form of cutaneous T-cell lymphoma (CTCL), has been associated with a variety of environmental and occupational exposures. Flame-retardant clothing (FRC), in contrast to flame-resistant clothing, is chemically treated and may constitute a previously unrecognized occupational hazard.ObjectivesTo report an association between FRC and MF.MethodsAfter encountering several young male patients whose onset of MF coincided with the occupational use of FRC and occupation as fire fighters, we did a retrospective search. Additional biopsy proven MF patients with use of FRC were identified by the EPIC electronic medical record using the search terms “CTCL, mycosis fungoides, flame, and flame-retardant.”ResultsEight MF patients, all males, ranging in age from 31 years to 64 years (median age, 35 years) with exposure to FRC were identified. MF remission was noted in three patients who discontinued FRC use and in one patient who used a cotton undershirt barrier, while disease persistence was noted in one patient who continued to use FRC.ConclusionsFRC appears to be associated with development of MF through chronic antigen stimulation. Use of FRC is an occupational hazard for fire fighters. Any patient whose MF coincides with use of FRC should avoid further exposure through avoidance or switching to clothing made from inherently flame-resistant fibers.

BATF controls T cell differentiation during chronic antigen stimulation

Abstract CD4+ T cells preserve self-tolerance in the periphery by exerting active suppression as regulatory T cells (Treg) or entering an inactive state known as anergy. Recent evidence suggests that anergy occurs naturally within a subpopulation of polyclonal CD4+ T cells and can generate precursors to Foxp3-expressing Treg cells. To identify transcription factors (TFs) underlying T cell anergy induction and its potential plasticity, we sorted polyclonal CD4+ T cell subsets from mice for downstream sequencing-based interrogation. Anergic CD44high Foxp3− CD73highFR4high Nrp1+ T cells were compared to effector-memory, Treg, and naïve T cell populations. Integrated ATAC-seq and RNA-seq analysis revealed a distinct program in the anergic T cell subpopulation. The anergy signature was driven by bZIP/AP-1 subfamily (Batf, Maf) and NFAT family (Nfatc1) transcription factors. Anergy-enriched TFs were then investigated in antigen-specific T cell tolerization systems where Batf knockdown led to altered expansion and minimal Treg cell differentiation. BATF was furthermore required for anergy-derived Foxp3+ Treg cell generation. Our data indicate that BATF orchestrates the transition to chronically-stimulated T cell differentiation states. Supported by grants from the NIH (T32 AI007313, P01 AI035296) and RRF (Future Physician Scientist Award)

Hallmark features of T cell dysfunction are established within hours after tumor antigen encounter

Abstract Tumor-specific CD8 T cells (TST) found in patients with cancer are dysfunctional and unable to halt cancer progression. TST dysfunction, also known as exhaustion, is encoded by specific epigenetic and transcriptional programs and thought to be induced by chronic antigen stimulation. Using a genetic liver cancer mouse model, we followed the fate of naïve TST in tumor-bearing hosts. Strikingly, we found that within hours after encountering tumor antigen, TST lost effector function, expressed high levels of inhibitory receptors, and displayed chromatin peak accessibility changes previously characterized in late-stage dysfunction. This rapid onset challenges the paradigm that chronic antigen/T cell receptor stimulation is required to induce dysfunction/exhaustion. Moreover, dysfunction-associated epigenetic features were established even prior to cell division, opposing the prevailing notion that cell divisions are required for epigenetic remodeling and T cell differentiation. To determine whether these early dysfunction hallmarks were “imprinted”, we reisolated TST from malignant lesions and transferred them into antigen-free hosts. While loss of effector function was imprinted within hours of tumor exposure, other dysfunctional hallmarks, including PD1 expression, required several days of tumor exposure and additional chromatin remodeling to become stably encoded. Our study reveals the rapid induction and epigenetic remodeling which underlies TST commitment to the dysfunctional fate, highlighting the need to target early activation-induced pathways to improve anti-cancer T cell immunity. Supported by T32GM007347-43

BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4 T cell responses to persistent antigen

Abstract Shortly after priming, the fate of activated CD4 T cells is segregated into BCL6+ follicular helper T (Tfh) and BCL6− effector (Teff) cells. However, it remains unknown how these subsets are sustained in the presence of chronic antigen stimulation. Using a combination of single cell- and population-based approaches, we show that in chronic viral infection, activated CD4 T cells differentiate into BCL6-dependent TCF-1+ progenitor cells with superior capacity to expand and give rise to both Teff and Tfh. They share properties with progenitor-exhausted CD8 T cells and are required for the continued generation of Teff cells as antigen persists. In response to tumors, an analogous CD4 T cell population develops in draining lymph nodes. Our study reveals the heterogeneity and plasticity of CD4 T cells upon encountering persistent antigen and highlights their population dynamics through a stable bipotent intermediate state.

Dysregulation of CD8+ T cell function in the setting of altered cytokine signaling due to inborn errors of immunity

Abstract A key outcome of chronic antigenic stimulation in the setting of sustained inflammation is the development of CD8+ T cell exhaustion. However, the relative roles of inflammation and antigen stimulation on T cell dysfunction remain unclear. Inborn errors of immunity (IEIs) provide an opportunity to study the effect of genetic alterations in signaling pathways on immune function. Here, we focus on an IEI resulting from genetically amplified cytokine signaling: gain-of-function mutations in STAT3 (STAT3 GOF). STAT3 signals downstream of multiple inflammatory cytokines (e.g., IL-6 and IL-27) and we used STAT3 GOF as a genetic mimic of chronic inflammation. To assess how amplified STAT3 signaling impacts immune cell subset distribution and activation status, PBMCs from STAT3 GOF patients and age-matched healthy controls were profiled via mass cytometry (CyTOF). This revealed altered states of CD8+ T cell activation including increased expression of immunoregulatory receptors (e.g., PD-1 and CD39). STAT3 GOF CD8+ T cells also showed impaired cytokine production and reduced proliferative capacity. Bulk RNA sequencing of naïve STAT3 GOF CD8+ T cells identified an exhausted-like transcriptional profile. Quantitation of metabolic function shows alterations in glucose use and oxidative phosphorylation in STAT3 GOF. Our studies suggest that inflammation alone may directly impair CD8+ T cell function. Understanding the mechanisms by which inflammation impacts T cell function may identify components of T cell dysregulation that can be targeted therapeutically in these rare patients, as well as those with more common inflammatory diseases (e.g., obesity) with shared aspects of T cell dysfunction. Supported by CHOP Research Institute, The Primary Immune Deficiency Treatment Consortium (PIDTC) and Immune Deficiency Foundation (IDF).

Autoimmunity, Infections, and the Risk of Monoclonal Gammopathy of Undetermined Significance.

Various epidemiological studies, including case reports and -series in addition to larger, population-based studies, have reported an increased prevalence of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma in individuals with a prior history of immune-related conditions. This is believed to support the role of chronic antigen stimulation in the pathogenesis of these conditions. In this short review, we summarize some of the largest population-based studies researching autoimmune diseases, infections, and the subsequent risk of MGUS, and discuss our understanding on its etiology and pathogenesis. Furthermore, we highlight important methodological limitations of previous studies in the field, but almost all studies on MGUS have been based on clinical, possibly biased, cohorts. Finally, we discuss future directions in researching the associations of MGUS and other disorders, including immune-related conditions, where screening studies play an important role.

Maladie de Sjögren : risque de lymphome et de myélome

Patients with Sjögren's disease (pSS) are at increased risk of lymphoid hemopathy. The development of lymphoma is the most serious complication of SJS. It occurs in 5 to 10% of the patients. Lymphomas in pSS are most often extra-nodal marginal zone non-Hodgkin's B-cell lymphomas that develop from the mucosa associated lymphoid tissue. They frequently occur in the salivary glands, which are the target organ of this autoimmune disease. The development of lymphoma in pSS is a multistep process related to chronic antigenic stimulation of B cells. This update reviews the main predictive factors for lymphoma in pSS and also the practical diagnostic and therapeutic management. In addition, it reviews the risk of myeloma in pSS, a much lesser known complication that is almost as common as lymphoma.

The Role of the Crosstalk Between Gut Microbiota and Immune Cells in the Pathogenesis and Treatment of Multiple Myeloma.

Around 10% of all hematologic malignancies are classified as multiple myeloma (MM), the second most common malignancy within that group. Although massive progress in developing of new drugs against MM has been made in recent years, MM is still an incurable disease, and every patient eventually has relapse refractory to any known treatment. That is why further and non-conventional research elucidating the role of new factors in MM pathogenesis is needed, facilitating discoveries of the new drugs. One of these factors is the gut microbiota, whose role in health and disease is still being explored. This review presents the continuous changes in the gut microbiota composition during our whole life with a particular focus on its impact on our immune system. Additionally, it mainly focuses on the chronic antigenic stimulation of B-cells as the leading mechanism responsible for MM promotion. The sophisticated interactions between microorganisms colonizing our gut, immune cells (dendritic cells, macrophages, neutrophils, T/B cells, plasma cells), and intestinal epithelial cells will be shown. That article summarizes the current knowledge about the initiation of MM cells, emphasizing the role of microorganisms in that process.

Large Granular Lymphocytic Leukemia: Current State of Diagnosis, Pathogenesis and Treatment.

This manuscript aims at updating the knowledge on the clinico-biological characteristics, pathogenesis, and the diagnostic challenges of T-LGLL and CLPD-NK disorders and reviews the advances in the management and treatment of these patients. It has been shown that clonal large granular lymphocyte (LGL) expansions arise from chronic antigenic stimulation, leading to resistance to apoptosis. All the above findings have facilitated the diagnosis of LGLL and provided insights in the pathogenesis of the disease. At present, there is no standard first-line therapy for the disease. Immunosuppressive agents are the treatment routinely used in clinical practice. However, these agents have a limited capacity to eradicate the LGL clone and induce long-lasting remission. Advances in the knowledge of pathogenesis have made it possible to explore new therapeutic targets with promising results. Since LGLL is a rare disease, international efforts are needed to carry on prospective clinical trials with new potentially active drugs that could include a large number of patients.