Promote T-cell Differentiation Research Articles

PA28γ induces dendritic cell maturation and activates T-cell immune responses in oral lichen planus.

Oral lichen planus (OLP) is a common chronic inflammatory disease of the oral mucosa, the mechanism of its inflammatory progression has not yet been fully elucidated. PA28γ plays a significant role in a variety of immune-related diseases. However, the exact role of PA28γ in the pathogenesis of OLP remains unclear. Here, we demonstrated that PA28γ is overexpressed in epithelial cells and inflammatory cells of OLP tissues but has no significant relationship with OLP subtypes. Functionally, keratinocytes with high PA28γ expression could induce dendritic cell (DC) maturation and promote the T-cell differentiation into Th1 cells in response to the immune response. In addition, we found that a high level of PA28γ expression is associated with high numbers of infiltrating mature DCs and activated T-cells in OLP tissues. Mechanistically, keratinocytes with high PA28γ expression could promote the secretion of C-C motif chemokine (CCL)5, blocking CCL5 or/and its receptor CD44 could inhibit the induction of T-cell differentiation by keratinocytes with high PA28γ expression. In conclusion, we reveal that keratinocytes with high expression of PA28γ in OLP can induce DC maturation and promote T-cell differentiation through the CCL5-CD44 pathway, providing previously unidentified mechanistic insights into the mechanism of inflammatory progression in OLP.

Role of dendritic cells in spinal cord injury.

Inflammation can worsen spinal cord injury (SCI), with dendritic cells (DCs) playing a crucial role in the inflammatory response. They mediate T lymphocyte differentiation, activate microglia, and release cytokines like NT-3. Moreover, DCs can promote neural stem cell survival and guide them toward neuron differentiation, positively impacting SCI outcomes. This review aims to summarize the role of DCs in SCI-related inflammation and identify potential therapeutic targets for treating SCI. Literature in PubMed and Web of Science was reviewed using critical terms related to DCs and SCI. The study indicates that DCs can activate microglia and astrocytes, promote T-cell differentiation, increase neurotrophin release at the injury site, and subsequently reduce secondary brain injury and enhance functional recovery in the spinal cord. This review highlights the repair mechanisms of DCs and their potential therapeutic potential for SCI.

Revealing the Mutually Enhanced Mechanism of Necroptosis and Immunotherapy Induced by Defect Engineering and Piezoelectric Effect.

Owing to low immunogenicity-induced immune escape and short-term circulating immune responses, the efficiency of immunotherapy is unsatisfactory. Therefore, triggering immunogenic cell death and establishing a long-term, mutually reinforced treatment modality are urgent challenges. In this study, ultrathin CaBi2 Nb2 O9 nanosheets with tunable oxygen vacancies (abbreviated as CBNO-OV1) are prepared for synergistic necroptosis and immunotherapy. The optimized vacancy concentration significantly improves the piezoelectric effect under ultrasound irradiation, thereby considerably improving the generation of reactive oxygen species (ROS). Density functional theory shows that oxygen vacancies can improve the efficiency of electron hole separation by suppressing their recombination, thus resulting in enhanced piezocatalytic activity. Moreover, the piezoelectric effect improves the permeability of tumor cell membranes, thus resulting in Ca2+ influx. Additionally, CBNO-OV1 also releases a portion of Ca2+ , which induces necroptosis assisted by explosive ROS. Ribonucleic acid transcription tests suggest the mechanisms associated with immune response activation and necroptosis. More importantly, necroptosis can trigger a significant immune response in vivo, thus activating macrophage M1 polarization through the NF-kappa B pathway and promoting T-cell differentiation.Tumor Necrosis Factor-α differentiated from macrophages conversely promotes necroptosis, thus realizing a mutually enhanced effect. This study demonstrates the feasibility of mutually reinforced necroptosis and immunotherapy for amplifying tumor efficacy.

Bifidobacterium animalis KV9 and Lactobacillus vaginalis FN3 alleviated β-lactoglobulin-induced allergy by modulating dendritic cells in mice.

Food allergy is a serious public health problem because of its high incidence and risk. Probiotics can induce immune regulation in patients with allergic diseases, but its mechanism is not fully clear. In this paper, β-lactoglobulin (β-LG)-sensitized mice were used as models to explore the mechanism of Bifidobacterium animalis KV9 (KV9) and Lactobacillus vaginalis FN3 (FN3) on reducing allergic reactions and regulating immune cell function. The results showed that oral administration of KV9 and FN3 significantly reduced the scores of allergic symptoms, hypothermia symptoms, and serum levels of β-LG-specific immunoglobulins E (β-LG-sIgE), histamine, and mast cell protease in allergic mice. Flow cytometry analysis of intestinal dendritic cells (DCs) showed that the proportion of CD11c+major histocompatibility complex (MHC)-II+DCs, CD11c+CD80+DCs, and CD11c+ CD86+DCs increased after KV9 and FN3 intervention, indicating that the strains induced immature DCs and decreased the antigen-presenting capacity of DCs. Meanwhile, the toll-like receptor 4 (TLR4)-NF-κB signaling pathway was activated in DCs. The secretion of interleukin-12 (IL-12) was significantly increased, while interleukin-4 (IL-4) was decreased by DCs after KV9 and FN3 intervention, indicating that DCs have the potential to promote T-cell differentiation into T helper type 1 (Th1) cells. Furthermore, the proportion of CD3+CD8−IFN-γ+ T cells in the spleen increased, while CD3+CD8−IL-4+T cells decreased after oral administration of KV9 and FN3, correcting the T helper type 2 (Th2)-skewed immune responses. These results indicate that KV9 and FN3 reduce β-LG-induced allergic symptoms in mice, and suggest that the two potential probiotics might be used as an alternative therapeutic agent for mitigating food allergy.

Peanut protein acts as a TH2 adjuvant by inducing RALDH2 in human antigen-presenting cells

Peanut is a potent inducer of proallergenic TH2 responses in susceptible individuals. Antigen-presenting cells (APCs) including dendritic cells and monocytes instruct naive Tcells to differentiate into various effector cells, determining immune responses such as allergy and tolerance. We sought to detect peanut protein (PN)-induced changes in gene expression in human myeloid dendritic cells (mDCs) and monocytes, identify signaling receptors that mediate these changes, and assess how PN-induced genes in mDCs impact their ability to promote T-cell differentiation. mDCs, monocytes, and naive CD4+ T cells were isolated from blood bank donors and peanut-allergic patients. APCs were incubated with PN and other stimulants, and gene expression was measured using microarray and RT quantitative PCR. To assess T-cell differentiation, mDCs were cocultured with naive TH cells. PN induced a unique gene expression profile in mDCs, including the gene that encodes retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in the retinoic acid (RA)-producing pathway. Stimulation of mDCs with PN also induced a 7-fold increase in the enzymatic activity of RALDH2. Blocking antibodies against Toll-like receptor (TLR)1/TLR2, as well as small interfering RNA targeting TLR1/TLR2, reduced the expression of RALDH2 in PN-stimulated APCs by 70%. Naive TH cells cocultured with PN-stimulated mDCs showed an RA-dependent 4-fold increase in production of IL-5 and expression of integrin α4β7. PN induces RALDH2 in human APCs by signaling through the TLR1/TLR2 heterodimer. This leads to production of RA, which acts on TH cells to induce IL-5 and gut-homing integrin. RALDH2 induction by PN in APCs and RA-promoted TH2 differentiation could be an important factor determining allergic responses to peanut.

Acetyl-11-keto-β-boswellic acid inhibits the secretion of cytokines by dendritic cells via the TLR7/8 pathway in an imiquimod-induced psoriasis mouse model and in vitro

AimsPsoriasis vulgaris is mediated by T and dendritic cells. This study aimed to investigate the effects of acetyl-11-keto-β-boswellic acid (AKBA) on activated dendritic cells (DCs) using an imiquimod (IMQ)-induced psoriasis-like mouse model and murine bone marrow–derived dendritic cells (BMDCs) stimulated with resiquimod (R848) in vitro. Materials and methodsThe mice were treated with IMQ and intragastrically administered 25–100 mg/kg/day of AKBA, 1 mg/kg/day of methotrexate (MTX), or normal saline. The inflammation of skin lesions in IMQ mice were evaluated by psoriasis area and severity index (PASI) and pathological staining. The related proteins of Toll-like receptor (TLR)7/8 pathways were assessed using Western blotting, and the expression levels of interleukin (IL)-23 and IL-12p40 mRNA using reverse transcription–polymerase chain reaction. The numbers of DCs and marker-positive BMDCs were assessed using flow cytometry and the levels of inflammatory factors using the enzyme-linked immunosorbent assay. Key findingsAKBA and MTX obviously improved the psoriasis-like skin lesions of IMQ-treated mice. AKBA also obviously decreased the PASI score, reduced the thickness of epidermis, ameliorated the infiltration of CD3+ and CD11c+ cells in skin lesions, decreased the activation of local DCs, inhibited the mRNA expression and secretion of inflammatory factors IL-12 and IL-23, inhibited the maturation and differentiation of DCs to promote T-cell differentiation, and inhibited the activation of TLR7/8 and IRF signaling pathways. SignificanceThis study implied that AKBA might have an anti-inflammatory effect on psoriasis by inhibiting the maturation and activation of DCs via the TLR8 and IRF signaling pathways.

Epigenetic dysregulation of ZEB1 is involved in LMO2-promoted T-cell acute lymphoblastic leukaemia leukaemogenesis

T-cell acute lymphoblastic leukaemia (T-ALL) is a hematological malignancy caused by the accumulation of genomic lesions that affect the development of T-cells. ZEB1, a member of zinc finger-homeodomain family transcription factor, exhibits crucial function in promoting T-cell differentiation and potentially acts as a tumor suppressor in T-ALL. However, the molecular mechanism by which ZEB1 regulates T-ALL leukaemogenesis remains obscure. Here, we showed that oncogenic LIM only 2 (LMO2) could recruit Sap18 and HDAC1 to assemble an epigenetic regulatory complex, thus inducing histone deacetylation in ZEB1 promoter and chromatin remodeling to achieve transcriptional repression. Furthermore, downregulation of ZEB1 by LMO2 complex results in an increased leukaemia stem cell (LSC) phenotype as well as unsensitivity in response to methotrexate (MTX) chemotherapy in T-ALL cells. Importantly, we demonstrated that Trichostatin A (TSA, a HDAC inhibitor) addition significantly attenuates MTX unsensitivity caused by dysfunction of LMO2/ZEB1 signaling. In conclusion, these findings have identified a molecular mechanism underlying LMO2/ZEB1-mediated leukaemogenesis, paving a way for treating T-ALL with a new strategy of epigenetic inhibitors.

Pim-1 inhibitor attenuates trinitrobenzene sulphonic acid induced colitis in the mice

Pim-1 kinase has been implicated in inflammatory bowel disease (IBD). This study aimed to evaluate the application of Pim-1 inhibitor (PIM-Inh) for the treatment of IBD. Mouse model of IBD was established by the treatment with trinitrobenzene sulphonic acid (TNBS). The results showed that disease activity index score was significantly decreased, colon length was significantly increased while Wallace score and pathological score were significantly decreased after PIM-Inh treatment compared to TNBS model group. In addition, GATA3 and ROR-γt mRNA and protein levels significantly increased but Foxp3 mRNA and protein levels significantly decreased in mice with TNBS treatment compared to mice without TNBS treatment. Administration of PIM-Inh caused significant decreases in GATA3, T-bet and ROR-γt mRNA and protein levels as well as significant increases in FOXP3 mRNA and protein levels. In conclusion, our data suggest that Pim-1 kinase inhibitor could attenuate IBD by promoting T-cell differentiation into Foxp3+ regulatory T-cells and is a promising agent for IBD therapy.

Angioimmunoblastic T cell lymphoma: novel molecular insights by mutation profiling.

Angioimmunoblastic T cell lymphoma (AITL) originates from follicular helper T-cells and is characterised by a polymorphic infiltrate with the neoplastic T-cells forming small clusters around the follicle and high endothelial venules. Despite the recent advances in its phenotypic characterisation, the genetics and molecular mechanisms underlying AITL are not fully understood. In the present study, we performed whole exome sequencing in 9 cases of AITL from Taiwan (n = 6) and U.K. (n = 3). We confirmed frequent mutations in TET2 (9/9), DNMT3A (3/9), IDH2 (3/9), RHOA (3/9) and PLCG1 (2/9) as recently reported by others. More importantly, we identified mutations in TNFRSF21 (1/9), CCND3 (1/9) and SAMSN1 (1/9), which are not yet seen or strongly implicated in the pathogenesis of AITL. Among the pathogenic mutations identified in AITL, mutations in DNA methylation regulators TET2 and DNMT3A occur early in hematopoietic stem cells as shown by previous studies, and these genetic events enhance the self-renewal of hematopoietic stem cells, but are unlikely to have any major impact on T-cell differentiation. Mutations in RHOA, PLCG1 and TNFRSF21 (DR6), which encode proteins critical for T-cell biology, most likely promote T-cell differentiation and malignant transformation, consequently generating the malignant phenotype. Our findings extend the molecular insights into the multistage development of AITL.

Butyrate and Mucosal Inflammation: New Scientific Evidence Supports Clinical Observation

Butyrate and Mucosal Inflammation: New Scientific Evidence Supports Clinical Observation

Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway.

Microbial metabolites such as short chain fatty acids (SCFAs) are highly produced in the intestine and potentially regulate the immune system. We studied the function of SCFAs in regulation of T cell differentiation into effector and regulatory T cells. We report that SCFAs can directly promote T cell differentiation into T cells producing IL-17, IFN-γ, and/or IL-10 depending on cytokine milieu. This effect of SCFAs on T cells is independent of GPR41- or GPR43 but dependent on direct histone deacetylase (HDAC) inhibitor activity. Inhibition of HDACs in T cells by SCFAs increased the acetylation of p70 S6 kinase and phosphorylation rS6, regulating the mTOR pathway required for generation of Th17, Th1, and IL-10+ T cells. Acetate (C2) administration enhanced the induction of Th1 and Th17 cells during C. rodentium infection but decreased anti-CD3-induced inflammation in an IL-10-dependent manner. Our results indicate that SCFAs promote T cell differentiation into both effector and regulatory T cells to promote either immunity or immune tolerance depending on immunological milieu.

Microbes and microbial effector molecules in treatment of inflammatory disorders

The healthy gut tolerates very large numbers of diverse bacterial species belonging mainly to the Bacteroidetes and Firmicutes phyla. These bacteria normally coexist peacefully with the gut and help maintain immune homeostasis and tolerance. The mechanisms promoting tolerance affect various cell populations, including the epithelial cells lining the gut, resident dendritic cells (DCs), and gut-homing T cells. Gut bacteria also influence multiple signaling pathways from Toll-like receptors to nuclear factor κB and regulate the functionality of DCs and T cells. Several bacterial species have been identified that promote T-cell differentiation, in particular T-helper 17 and T-regulatory cells. Insight into the molecular mechanisms by which bacteria mediate these effects will be very important in identifying new ways of treating intestinal and extra-intestinal immune-mediated diseases. These diseases are increasing dramatically in the human population and require new treatments. It may be possible in the future to identify specific bacterial species or strains that can correct for T-cell imbalances in the gut and promote immune homeostasis, both locally and systemically. In addition, new information describing microbial genomes affords the opportunity to mine for functional genes that may lead to new generation drugs relevant to a range of inflammatory disease conditions.

Identification of DeltaEF1 as a novel target that is negatively regulated by LMO2 in T‐cell leukemia

The lmo2 gene is a specific oncogene in T-cell leukemia, for its ectopic expression causes both increased pro-T-cell proliferation and differentiation arrest, leading to the onset of leukemia. Notably, DeltaEF1 (also known as ZEB1), a member of zinc finger-homeodomain family transcription factor, also exhibits crucial function in promoting T-cell differentiation. In this study, we found that DeltaEF1 was positively regulated by T-lineage-specific transcriptional regulator GATA3, while ectopically expressed LMO2 targeted to DeltaEF1 promoter by interaction with GATA3 and inhibited DeltaEF1 expression in transcriptional level. Moreover, LMO2 interacted with the N-terminal zinc finger domain of DeltaEF1 protein and inhibited its positive transcriptional regulatory function by this interaction. Taken together, our findings revealed that ectopically expressed LMO2 impaired the function of DeltaEF1 in both transcriptional and protein levels and identified DeltaEF1 as a novel pathogenic target of LMO2 in T-cell leukemia.

Generation of multi-functional antigen-specific human T-cells by lentiviral TCR gene transfer

T-cell receptor (TCR) gene transfer is an attractive strategy to generate antigen-specific T-cells for adoptive immunotherapy of cancer and chronic viral infection. However, current TCR gene transfer protocols trigger T-cell differentiation into terminally differentiated effector cells, which likely have reduced ability to mediate disease protection in vivo. We have developed a lentiviral gene transfer strategy to generate TCR-transduced human T-cells without promoting T-cell differentiation. We found that a combination of interleukin-15 (IL15) and IL21 facilitated lentiviral TCR gene transfer into non-proliferating T-cells. The transduced T-cells showed redirection of antigen specificity and produced IL2, IFNgamma and TNFalpha in a peptide-dependent manner. A significantly higher proportion of the IL15/IL21-stimulated T-cells were multi-functional and able to simultaneously produce all three cytokines (P<0.01), compared with TCR-transduced T-cells generated by conventional anti-CD3 plus IL2 stimulation, which primarily secreted only one cytokine. Similarly, IL15/IL21 maintained high levels of CD62L and CD28 expression in transduced T-cells, whereas anti-CD3 plus IL2 accelerated the loss of CD62L/CD28 expression. The data demonstrate that the combination of lentiviral TCR gene transfer together with IL15/IL21 stimulation can efficiently redirect the antigen specificity of resting primary human T-cells and generate multi-functional T-cells.

Notch Ligand Presenting Acellular 3D Microenvironments for ex vivo Human Hematopoietic Stem‐Cell Culture made by Layer‐By‐Layer Assembly

Development of in vitro human hematopoietic stem cell (HSC) niches that can recapitulate the bone marrow and thymus function is imperative for understanding the fundamental biology of human hematopoiesis. Currently most information of HSC self-renewal and lineage commitment has been primarily derived from murine studies where a substantial knowledge gap in humans still exists. Such established functional tissue analogues can also greatly serve as a valuable tool to identify specific signaling factors and their precise roles in hematopoiesis by systematically manipulating major experimental parameters. The thymus is a specialized organ providing unique environments for the development of T-lymphocytes from bone-marrow-derived HSCs. Although the precise nature of the thymic environment inducing T-cell differentiation remains uncertain, it has been identified that stromal cells and 3D microarchitecture play a critical role from numerous studies of ex vivo HSC cultures. For example, thymic stromal cells activate various cell-signaling processes through secreting growth factors and expressing membrane-bound ligands. Their 3D organization creates a distinctive intrathymic 3D microarchitecture that coordinates the aforementioned signaling milieus. Thymocytes passing through the interstices of the 3D network of thymic stroma undergo extensive physical contacts with stromal cells, which is the main mechanism to promote T-cell differentiation and maturation. Due to such complexity, until recently the only reliable in vitro culture model for successful T-cell differentiation was the fetal thymus organ culture (FTOC), which is composed of a 3D reaggregated dissection of fetal thymic tissues.

Short exposure to Notch ligand Delta-4 is sufficient to induce T-cell differentiation program and to increase the T cell potential of primary human CD34 + cells

The Notch pathway plays a key role in cell fate choices and in T-cell development. The goal of our study was to evaluate whether a short in vitro stimulation of the Notch pathway may alter human progenitor cell behavior. CD34+ cord blood progenitors were exposed for 4 days to either immobilized Notch ligand Delta-4 or in control conditions. Phenotypic and molecular changes induced by the short stimulation were assessed at day 4. Next, long-term alteration of the fate of these progenitors was assessed in culture conditions suitable for B (coculture with MS5 stromal cells) and T (FTOC and OP9 stromal cells expressing Delta-4 systems) cell differentiation. Notch activation was sufficient to trigger immunophenotypic and molecular changes consistent with early T-cell lineage differentiation. Delta-4 induced, in 4 days, CD7+cytCD3epsilon+ cells. This paralleled at the gene-transcription level with de novo expression of several T cell-related transcription factors and TCRgamma rearrangement, while B cell transcripts were simultaneous silenced. As compared to non-Delta-4 primed cells, these early changes translated to long-term alteration of the potential of cells. Delta-4 priming led to an acceleration of T-cell development, including a completion of the TCR rearrangement, when cells were cultured in systems suitable for T-cell development while B-cell development was inhibited. A transient Notch activation is sufficient to promote T-cell differentiation from cord blood CD34+ cells. This system may be a useful tool for the amplification and the quantification of the T potential of CD34+ cells in various disease conditions.

T-cell tolerance in allergic response.

Allergic diseases are immunological disorders (1), which originate from the activation of T-cell subsets secreting allergic, inflammatory factors including interleukin (IL)-4 and IL-5 and/or IL-13. The regulation of allergen-specific T cells is one of the strategies to control disease. However, available drugs such as steroids are not allergen-specific and only temporarily suppress the activity of immune cells. Thus, they are not curative and accompanied by side effects. In contrast, allergen-specific immunotherapy (SIT) can specifically restore normal immunity against allergens. Successful SIT is characterized by the induction of peripheral T-cell tolerance against the allergen (2, 3). Although successful SIT applies predominantly for treatment of monoor oligo-specific allergies, the underlying immuno-regulatory mechanism can possibly be projected on allergic disease in general. Lymphocyte tolerance describes a complex process, which balances the reactivity against foreign vs. autologous antigens. Autoreactive lymphocytes are eliminated early in their thymic development, a process, which is covered by the term central tolerance (4). T cells, however, might escape thymic selection or might face harmless antigens later in their development, which are meant to be under the control of peripheral tolerance (5). Lymphocyte tolerance is likely to be a dynamic process (6), which adapts to the development of the organism to effectively distinguish autologous from foreign antigens. Recent investigations on peripheral tolerance revealed several basic mechanisms. These mechanisms comprise cell survival, as cells might undergo apoptosis, which would delete antigen specificities. Furthermore, antigens located in anatomically ‘hidden’ areas could be neglected by the immune system. Finally, cells could be suppressed and/or undergo clonal anergy, which keeps already existing lymphocyte specificities under control (7–9). The latter mechanism appears to be particularly interesting for the understanding of the pathogenesis of allergic disease, because allergenspecific T cells can be isolated, even from donors, who do not suffer from allergies. Moreover, it is frequently observed that patients are sensitized against two allergens but only show clinical symptoms against one of them. Interestingly, both the clinically silent and the pathogenic T-cell specificities, express both Th2-like cytokines.

Understanding the mechanism of the age-change of thymic function to promote T cell differentiation

Immunological functions peak at around puberty and gradually decline thereafter with advancing age. The immunological decline mainly occurs in the T cell-dependent immune system and is generally associated with an increase in not only susceptibility to infections but also incidence of autoimmune phenomena. The age-related changes in T-cell dependent immune functions can be mainly ascribed to the physiological thymic involution which starts in the early phase of life. The age-related thymic involution can be ascribed to either extrinsic or intrinsic factors. Bone marrow stem cells can be one of the extrinsic factors for the thymic involution, but their role is estimated to be marginal as compared with alteration of the thymic microenvironment. With advancing age, the thymic capacity to promote T-cell differentiation declines together with a change in the composition of T-cell subsets produced. Such an alteration of the thymic environment is responsible for the age-related change in peripheral T cells in number and in composition. Age change is observed in several intrinsic factors in the thymic environment which influence proliferation of thymocytes. These thymic intrinsic factors can either promote or inhibit proliferation of thymocytes, and promoting factors generally decrease with age with a concomitant increase in inhibitory factors. Various endocrine hormones are important extrinsic factors influencing the thymic function. In fact, physiological thymic involution can be intervened by manipulation of the endocrine system, sometimes resulting in rejuvenation of immune functions to a certain extent. A specific strain of Buffalo rats has an unusual thymus, which does not involute with age, and the functions of the T-cell dependent immune system do not decline with age. Such animals having hyperplastic thymus are relatively resistant to various kinds of stress. Thus, restoration of immune functions in the aged animals appears to be beneficial for them in coping with various diseases associated with age.

Influence of age of thymic grafts on the differentiation of T cells in nude mice

Age-related changes in the capacity of thymic grafts to promote T-cell differentiation were studied in congenic nude BALB/c mice. The results revealed that the cytolytic T-cell activity and T-cell-dependent anti-SRBC response declined exponentially with age, the former starting its decline at birth, and the latter after adulthood. In contrast, the T-cell-dependent mitogenic response to PHA and Con A stimulation and the number of Thy-1 + cells declined minimally with age of the thymic graft. These findings suggest that aging decreases the capacity of the thymus to synthesize the various factors needed for the generation of T-cell subpopulations differently with respect to the time of onset and rate of decline. In addition, results suggest that the aging thymus is also losing its ability to regulate natural killer cells.

Induction of ecto-5′-nucleotidase activity in human thymocytes

Ecto-5′-nucleotidase represents a marker of human T-cell maturation with intrathymic T lymphocytes expressing significantly lower activities than mature, peripheral blood T cells. We determined if thymic epithelial cell-derived factors, known to promote T-cell differentiation, could influence the expression of 5′-nucleotidase by human thymocytes. Human thymic epithelium-conditioned medium and thymosin were capable of inducing a two- to threefold increase in enzyme activity compared to controls. These data suggest a role for thymic humoral factors in the expression of 5′-nucleotidase activity during T-cell maturation.