Peripheral Non-lymphoid Tissues Research Articles

Tertiary lymphoid structures in cancer: maturation and induction.

Tertiary lymphoid structure (TLS) is an ectopic lymphocyte aggregate formed in peripheral non-lymphoid tissues, including inflamed or cancerous tissue. Tumor-associated TLS serves as a prominent center of antigen presentation and adaptive immune activation within the periphery, which has exhibited positive prognostic value in various cancers. In recent years, the concept of maturity regarding TLS has been proposed and mature TLS, characterized by well-developed germinal centers, exhibits a more potent tumor-suppressive capacity with stronger significance. Meanwhile, more and more evidence showed that TLS can be induced by therapeutic interventions during cancer treatments. Thus, the evaluation of TLS maturity and the therapeutic interventions that induce its formation are critical issues in current TLS research. In this review, we aim to provide a comprehensive summary of the existing classifications for TLS maturity and therapeutic strategies capable of inducing its formation in tumors.

Abstract 6433: Anti-CD36 monoclonal antibody can sensitize the neoadjuvant chemotherapy response in PDAC by eliminating the senescent tertiary lymphatic structure

Abstract Objective: Pancreatic ductal adenocarcinoma (PDAC) is deadly and aggressive. Neoadjuvant chemotherapy (NAC) may reduce tumor volume and alter the resectability of the tumor. The efficacy of neoadjuvant chemotherapy in patients is still limited. Tertiary lymphoid structures (TLSs) develop in peripheral non-lymphoid tissues and are essential for the immune response and correlate with chemotherapy in various tumor types. However, more research is needed to determine how TLSs affect neoadjuvant chemotherapy in PDAC. We aim to determine how neoadjuvant chemotherapy affects tumor-infiltrating lymphocytes (TLSs) in PDAC patients. We also want to find a biomarker to boost PDAC neoadjuvant chemotherapy response. Methods: We retrospectively collected formalin-fixed paraffin embedded (FFPE) tissues from 115 PDAC patients without preoperative treatment and 72 patients pretreated with neoadjuvant chemotherapy. Multispectral images were processed using AI-powered image analysis software (Tissue Gnostics; Zeiss, Germany). The 10X Genomics platform was used to sequence single cells in tissue samples from five patients who received neoadjuvant chemotherapy (NAC) and five patients who had not received any treatment before analysis (pretreatment naïve, PN). TLS was separated using Laser Microdissection. The mouse model was created by orthotopically injecting tumor cells into the pancreas. Results: Patients who received NAC have a senescent microenvironment. High-throughput single-cell sequencing showed that the senescent gene signature score was enriched in the NAC group, especially in immune cells. The percentage of p16+ CD20+ B cells and P16+ CD3+ T cells in TLSs also increased in the NAC group. Spatial transcriptomics analysis exhibited that CD36 is highly expressed in senescent TLSs, which suggested that CD36 may be a marker for senescent TLSs. Moreover, CD36+ TLSs induced the infiltration of MDSCs and regulatory T cells. CD36+ TLSs were an independent prognostic factor for poor overall survival (OS) (HR=0.67, p=0.002) and progression-free survival (PFS) (HR=0.71, p=0.003). A mice orthotopic xenograft model showed that an anti-CD36 monoclonal antibody eliminated senescent TLSs in pancreatic tissue. MDSCs and Tregs in the surrounding tissue also decreased. Additionally, in vivo KPC mice model showed that the combination of an anti-CD36 and chemotherapy reduced tumor volume and increased survival compared to chemotherapy alone. Conclusion: NAC has the potential to induce the senescence of tumor-associated TLSs, a phenomenon that has been linked to unfavorable prognosis in PDAC. CD36 serves as a viable marker for senescent TLSs that can be targeted. The administration of an anti-CD36 monoclonal antibody can potentially enhance the efficacy of chemotherapy in PDAC by selectively eliminating CD36+ senescent TLSs in mouse models. Citation Format: Jingrui Yan, Tianxing Zhou, Chao Yang, Yongjie Xie, Jun Yu, Jihui Hao. Anti-CD36 monoclonal antibody can sensitize the neoadjuvant chemotherapy response in PDAC by eliminating the senescent tertiary lymphatic structure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6433.

Tissue-Resident Memory T Cells in Allergy.

Tissue-resident memory T (TRM) cells constitute a distinct subset within the memory T cell population, serving as the vanguard against invading pathogens and antigens in peripheral non-lymphoid tissues, including the respiratory tract, intestines, and skin. Notably, TRM cells adapt to the specific microenvironment of each tissue, predominantly maintaining a sessile state with distinctive phenotypic and functional attributes. Their role is to ensure continuous immunological surveillance and protection. Recent findings have highlighted the pivotal contribution of TRM cells to the modulation of adaptive immune responses in allergic disorders such as allergic rhinitis, asthma, and dermatitis. A comprehensive understanding of the involvement of TRM cells in allergic diseases bears profound implications for allergy prevention and treatment. This review comprehensively explores the phenotypic characteristics, developmental mechanisms, and functional roles of TRM cells, focusing on their intricate relationship with allergic diseases.

Mouse Memory CD8 T Cell Subsets Defined by Tissue-Resident Memory Integrin Expression Exhibit Distinct Metabolic Profiles.

Tissue-resident memory CD8 T cells (TRM) principally reside in peripheral nonlymphoid tissues, such as lung and skin, and confer protection against a variety of illnesses ranging from infections to cancers. The functions of different memory CD8 T cell subsets have been linked with distinct metabolic pathways and differ from other CD8 T cell subsets. For example, skin-derived memory T cells undergo fatty acid oxidation and oxidative phosphorylation to a greater degree than circulating memory and naive cells. Lung TRMs defined by the cell-surface expression of integrins exist as distinct subsets that differ in gene expression and function. We hypothesize that TRM subsets with different integrin profiles will use unique metabolic programs. To test this, differential expression and pathway analysis were conducted on RNA sequencing datasets from mouse lung TRMs yielding significant differences related to metabolism. Next, metabolic models were constructed, and the predictions were interrogated using functional metabolite uptake assays. The levels of oxidative phosphorylation, mitochondrial mass, and neutral lipids were measured. Furthermore, to investigate the potential relationships to TRM development, T cell differentiation studies were conducted invitro with varying concentrations of metabolites. These demonstrated that lipid conditions impact T cell survival, and that glucose concentration impacts the expression of canonical TRM marker CD49a, with no effect on central memory-like T cell marker CCR7. In summary, it is demonstrated that mouse resident memory T cell subsets defined by integrin expression in the lung have unique metabolic profiles, and that nutrient abundance can alter differentiation.

Tissue-resident memory T cells in chronic liver diseases: Phenotype, development and function.

Tissue-resident memory (TRM) T cells are a unique subset of memory T cells that are critical for the first line of defense against pathogens or antigens in peripheral non-lymphoid tissues such as liver, gut, and skin. Generally, TRM cells are well adapted to the local environment in a tissue-specific manner and typically do not circulate but persist in tissues, distinguishing them from other memory T cell lineages. There is strong evidence that liver TRM cells provide a robust adaptive immune response to potential threats. Indeed, the potent effector function of hepatic TRM cells makes it essential for chronic liver diseases, including viral and parasite infection, autoimmune liver diseases (AILD), nonalcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC) and liver transplantation. Manipulation of hepatic TRM cells might provide novel promising strategies for precision immunotherapy of chronic liver diseases. Here, we provide insights into the phenotype of hepatic TRM cells through surface markers, transcriptional profiles and effector functions, discuss the development of hepatic TRM cells in terms of cellular origin and factors affecting their development, analyze the role of hepatic TRM cells in chronic liver diseases, as well as share our perspectives on the current status of hepatic TRM cell research.

CXCR6 is required for tissue resident memory T cell formation across diverse peripheral non-lymphoid tissues

Abstract CD8 T cell control of viral infections in peripheral tissues is largely dependent upon their spatial positioning. Clearance of pathogens requires direct contact between CD8 T cells and infected cells. Chemokine receptors play an essential role in this process by facilitating T cell entry into tissues, directing T cell positioning within tissues and by influencing egress out of tissues. Tissue resident memory T cells (TRM), which fail to egress after pathogen clearance and scan cells for signs of infection, are potent sources of immunity to secondary encounters with pathogens. Here we show that expression of the chemokine receptor CXCR6 is a conserved feature of TRM after viral infection in many non-lymphoid tissues. Using CXCR6KO TCR-tg T cells, we found that CXCR6 is necessary for proper formation of TRM in all non-lymphoid tissues examined. CXCR6 was necessary for early accumulation of effector T cells in several tissues such as the kidney and salivary gland but CXCR6 was dispensable for early accumulation in the skin. After vaccinia infection in the skin, CXCR6 expression is reinforced upon antigen re-encounter and promotes CD8 T cell accumulation in a migration-independent manner. Using single cell transcriptional analysis, we show that CXCR6KO TRM appear to exhibit a survival disadvantage and are outcompeted by wildtype T cells. This work reveals a critical requirement for generating TRM in diverse anatomical locations and may benefit strategies for vaccine design, anti-tumor immunity and reducing T-cell mediated autoimmunity. Supported by R01CA238163 T32Al100853-10

The Diverse Roles of γδ T Cells in Cancer: From Rapid Immunity to Aggressive Lymphoma.

Simple Summaryγδ T cells play important roles in cancer immunity. Their rapid activation and cytotoxic nature make them promising candidates for use in cell-based immunotherapies; however, under certain conditions, they can induce pro-tumour functions. Furthermore, upon transformation, γδ T cells can develop into aggressive lymphomas with a poor prognosis and no curative therapeutic options. Here, we provide a comprehensive summary of our current knowledge on the complex roles of γδ T cells in cancer. We discuss their anti- and pro-tumour functions in both solid and blood cancers, highlighting the key subsets involved and their potential utility in anti-cancer immunotherapy. We also discuss the mechanisms of γδ T-cell transformation, summarising the resulting γδ T-cell leukaemia/lymphoma entities and their genetic and molecular profiles, as well as current and future treatment strategies.γδ T cells are unique players in shaping immune responses, lying at the intersection between innate and adaptive immunity. Unlike conventional αβ T cells, γδ T cells largely populate non-lymphoid peripheral tissues, demonstrating tissue specificity, and they respond to ligands in an MHC-independent manner. γδ T cells display rapid activation and effector functions, with a capacity for cytotoxic anti-tumour responses and production of inflammatory cytokines such as IFN-γ or IL-17. Their rapid cytotoxic nature makes them attractive cells for use in anti-cancer immunotherapies. However, upon transformation, γδ T cells can give rise to highly aggressive lymphomas. These rare malignancies often display poor patient survival, and no curative therapies exist. In this review, we discuss the diverse roles of γδ T cells in immune surveillance and response, with a particular focus on cancer immunity. We summarise the intriguing dichotomy between pro- and anti-tumour functions of γδ T cells in solid and haematological cancers, highlighting the key subsets involved. Finally, we discuss potential drivers of γδ T-cell transformation, summarising the main γδ T-cell lymphoma/leukaemia entities, their clinical features, recent advances in mapping their molecular and genomic landscapes, current treatment strategies and potential future targeting options.

Ex Vivo Expanded Donor Alloreactive Regulatory T Cells Lose Immunoregulatory, Proliferation, and Antiapoptotic Markers After Infusion Into ATG-lymphodepleted, Nonhuman Primate Heart Allograft Recipients.

Regulatory T cell (Treg) therapy is a promising approach to amelioration of allograft rejection and promotion of organ transplant tolerance. However, the fate of infused Treg, and how this relates to their therapeutic efficacy using different immunosuppressive regimens is poorly understood. Our aim was to analyze the tissue distribution, persistence, replicative activity and phenotypic stability of autologous, donor antigen alloreactive Treg (darTreg) in anti-thymocyte globulin (ATG)-lymphodepleted, heart-allografted cynomolgus monkeys. darTreg were expanded ex vivo from flow-sorted, circulating Treg using activated donor B cells and infused posttransplant into recipients of major histocompatibility complex-mismatched heart allografts. Fluorochrome-labeled darTreg were identified and characterized in peripheral blood, lymphoid, and nonlymphoid tissues and the graft by flow cytometric analysis. darTreg selectively suppressed autologous T cell responses to donor antigens in vitro. However, following their adoptive transfer after transplantation, graft survival was not prolonged. Early (within 2 wk posttransplant; under ATG, tacrolimus, and anti-IL-6R) or delayed (6-8 wk posttransplant; under rapamycin) darTreg infusion resulted in a rapid decline in transferred darTreg in peripheral blood. Following their early or delayed infusion, labeled cells were evident in lymphoid and nonlymphoid organs and the graft at low percentages (<4% CD4+ T cells). Notably, infused darTreg showed reduced expression of immunoregulatory molecules (Foxp3 and CTLA4), Helios, the proliferative marker Ki67 and antiapoptotic Bcl2, compared with preinfusion darTreg and endogenous CD4+CD25hi Treg. Lack of therapeutic efficacy of infused darTreg in lymphodepleted heart graft recipients appears to reflect loss of a regulatory signature and proliferative and survival capacity shortly after infusion.

Tissue Tregs and Maintenance of Tissue Homeostasis.

Regulatory T cells (Tregs) specifically expressing Forkhead box P3 (Foxp3) play roles in suppressing the immune response and maintaining immune homeostasis. After maturation in the thymus, Tregs leave the thymus and migrate to lymphoid tissues or non-lymphoid tissues. Increasing evidence indicates that Tregs with unique characteristics also have significant effects on non-lymphoid peripheral tissues. Tissue-resident Tregs, also called tissue Tregs, do not recirculate in the blood or lymphatics and attain a unique phenotype distinct from common Tregs in circulation. This review first summarizes the phenotype, function, and cytokine expression of these Tregs in visceral adipose tissue, skin, muscle, and other tissues. Then, how Tregs are generated, home, and are attracted to and remain resident in the tissue are discussed. Finally, how an increased understanding of these tissue Tregs might guide clinical treatment is discussed.

Afferent Lymphatic Transport and Peripheral Tissue Immunity.

Lymphatic vessels provide an anatomical framework for immune surveillance and adaptive immune responses. Although appreciated as the route for Ag and dendritic cell transport, peripheral lymphatic vessels are often not considered active players in immune surveillance. Lymphatic vessels, however, integrate contextual cues that directly regulate transport, including changes in intrinsic pumping and capillary remodeling, and express a dynamic repertoire of inflammatory chemokines and adhesion molecules that facilitates leukocyte egress out of inflamed tissue. These mechanisms together contribute to the course of peripheral tissue immunity. In this review, we focus on context-dependent mechanisms that regulate fluid and cellular transport out of peripheral nonlymphoid tissues to provide a framework for understanding the effects of afferent lymphatic transport on immune surveillance, peripheral tissue inflammation, and adaptive immunity.

Aging, Immunity, and COVID-19: How Age Influences the Host Immune Response to Coronavirus Infections?

The novel coronavirus severe acute respiratory syndrome coronavirus 2 causing the Coronavirus disease (COVID-19) pandemic has ravaged the world with over 72 million total cases and over 1.6 million deaths worldwide as of early December 2020. An overwhelming preponderance of cases and deaths is observed within the elderly population, and especially in those with pre-existing conditions and comorbidities. Aging causes numerous biological changes in the immune system, which are linked to age-related illnesses and susceptibility to infectious diseases. Age-related changes influence the host immune response and therefore not only weaken the ability to fight respiratory infections but also to mount effective responses to vaccines. Immunosenescence and inflamm-aging are considered key features of the aging immune system wherein accumulation of senescent immune cells contribute to its decline and simultaneously increased inflammatory phenotypes cause immune dysfunction. Age-related quantitative and qualitative changes in the immune system affect cells and soluble mediators of both the innate and adaptive immune responses within lymphoid and non-lymphoid peripheral tissues. These changes determine not only the susceptibility to infections, but also disease progression and clinical outcomes thereafter. Furthermore, the response to therapeutics and the immune response to vaccines are influenced by age-related changes within the immune system. Therefore, better understanding of the pathophysiology of aging and the immune response will not only help understand age-related diseases but also guide targeted management strategies for deadly infectious diseases like COVID-19.

Human T cells interacting with HNSCC‐derived mesenchymal stromal cells acquire tissue‐resident memory like properties

Tissue-resident memory (Trm) cells are specialized components of both CD4+ and CD8+ T cell subsets that persist in peripheral nonlymphoid tissues following infections and provide fast response in case of a secondary invasion by the same pathogen. Trm cells express the surface markers CD69, CD103, and the immune checkpoint molecule PD-1. Trm cells develop not only in the context of infections but also in tumors, where they can provide a line of defense as suggested by the positive correlation between the frequency of tumor-infiltrating Trm cells and patients' survival. Trm cells persistence in peripheral tissues depends on their adaptation to the local microenvironment and the presence of survival factors, mainly IL-7, IL-15, and Notch ligands. However, the cell sources of these factors are largely unknown, especially in the context of tumors. Here, we show that head-neck squamous cell carcinoma (HNSCC) is enriched in CD4+ and CD8+ T cells with a Trm phenotype. Moreover, we show that mesenchymal stromal cells that accumulate in HNSCC are a source of survival factors and allow proper expression of Trm-typical markers in a VCAM1-dependent manner.

Sepsis Triggers a Late Expansion of Functionally Impaired Tissue-Vascular Inflammatory Monocytes During Clinical Recovery

Sepsis is characterized by a systemic inflammation that can cause an immune dysfunction, for which the underlying mechanisms are unclear. We investigated the impact of cecal ligature and puncture (CLP)-mediated polymicrobial sepsis on monocyte (Mo) mobilization and functions. Our results show that CLP led to two consecutive phases of Mo deployment. The first one occurred within the first 3 days after the induction of the peritonitis, while the second phase was of a larger amplitude and extended up to a month after apparent clinical recovery. The latter was associated with the expansion of Mo in the tissue reservoirs (bone marrow and spleen), their release in the blood and their accumulation in the vasculature of peripheral non-lymphoid tissues. It occurred even after antibiotic treatment but relied on inflammatory-dependent pathways and inversely correlated with increased susceptibility and severity to a secondary infection. The intravascular lung Mo displayed limited activation capacity, impaired phagocytic functions and failed to transfer efficient protection against a secondary infection into monocytopenic CCR2-deficient mice. In conclusion, our work unveiled key dysfunctions of intravascular inflammatory Mo during the recovery phase of sepsis and provided new insights to improve patient protection against secondary infections.

Toward the Existence of a Sympathetic Neuroplasticity Adaptive Mechanism Influencing the Immune Response. A Hypothetical View-Part I.

The nervous system exerts a profound influence on the function of the immune system (IS), mainly through the sympathetic arm of the autonomic nervous system. In fact, the sympathetic nervous system richly innervates secondary lymphoid organs (SLOs) such as the spleen and lymph nodes. For decades, different research groups working in the field have consistently reported changes in the sympathetic innervation of the SLOs during the activation of the IS, which are characterized by a decreased noradrenergic activity and retraction of these fibers. Most of these groups interpreted these changes as a pathological phenomenon, referred to as “damage” or “injury” of the noradrenergic fibers. Some of them postulated that this “injury” was probably due to toxic effects of released endogenous mediators. Others, working on animal models of chronic stimulation of the IS, linked it to the very chronic nature of processes. Unlike these views, this first part of the present work reviews evidence which supports the hypothesis of a specific adaptive mechanism of neural plasticity from sympathetic fibers innervating SLOs, encompassing structural and functional changes of noradrenergic nerves. This plasticity mechanism would involve segmental retraction and degeneration of these fibers during the activation of the IS with subsequent regeneration once the steady state is recovered. The candidate molecules likely to mediate this phenomenon are also here introduced. The second part will extend this view as to the potential changes in sympathetic innervation likely to occur in inflamed non-lymphoid peripheral tissues and its possible immunological implications.

Toward the Existence of a Sympathetic Neuroplasticity Adaptive Mechanism Influencing the Immune Response. A Hypothetical View-Part II.

In the preceding work, a hypothesis on the existence of a specific neural plasticity program from sympathetic fibers innervating secondary lymphoid organs was introduced. This proposed adaptive mechanism would involve segmental retraction and degeneration of noradrenergic terminals during the immune system (IS) activation followed by regeneration once the IS returns to the steady-state. Starting from such view, this second part presents clinical and experimental evidence allowing to envision that this sympathetic neural plasticity mechanism is also operative on inflamed non-lymphoid peripheral tissues. Importantly, the sympathetic nervous system regulates most of the physiological bodily functions, ranging from cardiovascular, respiratory and gastro-intestinal functions to endocrine and metabolic ones, among others. Thus, it seems sensible to think that compensatory programs should be put into place during inflammation in non-lymphoid tissues as well, to avoid the possible detrimental consequences of a sympathetic blockade. Nevertheless, in many pathological scenarios like severe sepsis, chronic inflammatory diseases, or maladaptive immune responses, such compensatory programs against noradrenergic transmission impairment would fail to develop. This would lead to a manifest sympathetic dysfunction in the above-mentioned settings, partly accounting for their underlying pathophysiological basis; which is also discussed. The physiological/teleological significance for the whole neural plasticity process is postulated, as well.

Innate lymphoid cell sensing of tissue vitality.

Innate lymphoid cells (ILCs) constitute a heterogeneous population of cytokine-secreting cells that colonize different tissues and are heavily reliant on cytokines and other secreted factors for their development, maintenance and effector functions. Most ILCs are tissue resident and differentiate in non-lymphoid peripheral tissues. As tissue-resident sentinels, ILCs must rapidly identify pathogens or malignancy in an effort to return the tissue to homeostasis. Here we review the mechanisms that ILCs employ to sense cytokines and other potent immunoregulatory factors that promote their development in different tissues as well as the ability to distinguish pathogenic versus healthy tissue microenvironments and highlight the importance of these pathways for human disease.

The Nontoxic Cholera B Subunit Is a Potent Adjuvant for Intradermal DC-Targeted Vaccination.

CD4+ T cells are major players in the immune response against several diseases; including AIDS, leishmaniasis, tuberculosis, influenza and cancer. Their activation has been successfully achieved by administering antigen coupled with antibodies, against DC-specific receptors in combination with adjuvants. Unfortunately, most of the adjuvants used so far in experimental models are unsuitable for human use. Therefore, human DC-targeted vaccination awaits the description of potent, yet nontoxic adjuvants. The nontoxic cholera B subunit (CTB) can be safely used in humans and it has the potential to activate CD4+ T cell responses. However, it remains unclear whether CTB can promote DC activation and can act as an adjuvant for DC-targeted antigens. Here, we evaluated the CTB's capacity to activate DCs and CD4+ T cell responses, and to generate long-lasting protective immunity. Intradermal (i.d.) administration of CTB promoted late and prolonged activation and accumulation of skin and lymphoid-resident DCs. When CTB was co-administered with anti-DEC205-OVA, it promoted CD4+ T cell expansion, differentiation, and infiltration to peripheral nonlymphoid tissues, i.e., the skin, lungs and intestine. Indeed, CTB promoted a polyfunctional CD4+ T cell response, including the priming of Th1 and Th17 cells, as well as resident memory T (RM) cell differentiation in peripheral nonlymphoid tissues. It is worth noting that CTB together with a DC-targeted antigen promoted local and systemic protection against experimental melanoma and murine rotavirus. We conclude that CTB administered i.d. can be used as an adjuvant to DC-targeted antigens for the induction of broad CD4+ T cell responses as well as for promoting long-lasting protective immunity.

CD8+ Resident Memory T Cells and Viral Infection.

Tissue-resident memory T (Trm) cells are a subset of recently identified memory T cells that mainly reside and serve as sentinels in non-lymphoid peripheral tissues. Unlike the well-characterized circulating central memory T (Tcm) cells and effector memory T (Tem) cells, Trm cells persist in the tissues, do not recirculate into blood, and offer immediate protection against pathogens upon reinfection. In this review, we focus on CD8+ Trm cells and briefly introduce their characteristics, development, maintenance, and function during viral infection. We also discuss some unresolved problems, such as how CD8+ Trm cells adapt to the local tissue microenvironment, how Trm cells interact with other immune cells during their development and maintenance, and the mechanisms by which CD8+ Trm cells confer immune protection. We believe that a better understanding of these problems is of great clinical and therapeutic value and may contribute to more effective vaccination and treatments against viral infection.

A Systematic Review: The Role of Resident Memory T Cells in Infectious Diseases and Their Relevance for Vaccine Development.

Resident memory T cells have emerged as key players in the immune response generated against a number of pathogens. Their ability to take residence in non-lymphoid peripheral tissues allows for the rapid deployment of secondary effector responses at the site of pathogen entry. This ability to provide enhanced regional immunity has gathered much attention, with the generation of resident memory T cells being the goal of many novel vaccines. This review aimed to systematically analyze published literature investigating the role of resident memory T cells in human infectious diseases. Known effector responses mounted by these cells are summarized and key strategies that are potentially influential in the rational design of resident memory T cell inducing vaccines have also been highlighted. A Boolean search was applied to Medline, SCOPUS, and Web of Science. Studies that investigated the effector response generated by resident memory T cells and/or evaluated strategies for inducing these cells were included irrespective of published date. Studies must have utilized an established technique for identifying resident memory T cells such as T cell phenotyping. While over 600 publications were revealed by the search, 147 articles were eligible for inclusion. The reference lists of included articles were also screened for other eligible publications. This resulted in the inclusion of publications that studied resident memory T cells in the context of over 25 human pathogens. The vast majority of studies were conducted in mouse models and demonstrated that resident memory T cells mount protective immune responses. Although the role resident memory T cells play in providing immunity varies depending on the pathogen and anatomical location they resided in, the evidence overall suggests that these cells are vital for the timely and optimal protection against a number of infectious diseases. The induction of resident memory T cells should be further investigated and seriously considered when designing new vaccines.

TCF/LEF family transcription factors in peripheral Treg homeostasis

Abstract CD4+Foxp3+ regulatory T cells (Tregs) are key players in preventing lethal autoimmunity and excessive inflammation. However, the homeostatic dynamics of Tregs in peripheral lymphoid and non-lymphoid tissues remains poorly defined. We here report that two TCF/LEF family transcription factors, LEF1 and TCF1, play critical roles in this process. Our studies led to a revised “three-stage” model of Treg peripheral differentiation, delineated by the gradient expressions of LEF1 and TCF1. We found that LEF1− TCF1− subset was bona fide effector Tregs and exhibited a core gene signature shared by various tissue Tregs. Transcriptome and conditional knockout analyses revealed that TCF1 and LEF1 may each control segregated clusters of Treg genes and regulate Treg differentiation in a “division of labor” manner. Together, these data provide novel insights into transcriptional regulation of Treg homeostasis and function.