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T cells are critical in orchestrating protective immune responses to cancer and an array of pathogens. The interaction between a peptide MHC (pMHC) complex on antigen presenting cells (APCs) and T cell receptors (TCRs) on T cells initiates T cell activation, division, and clonal expansion in secondary lymphoid organs. T cells must also integrate multiple T cell-intrinsic and extrinsic signals to acquire the effector functions essential for the defense against invading microbes. In the case of T helper cell differentiation, while innate cytokines have been demonstrated to shape effector CD4 T lymphocyte function, the contribution of TCR signaling strength to T helper cell differentiation is less understood. In this review, we summarize the signaling cascades regulated by the strength of TCR stimulation. Various mechanisms in which TCR signal strength controls T helper cell expansion and differentiation are also discussed.

Inherited CTPS1, CD27, and CD70 deficiencies in humans have revealed key factors of T‐lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein–Barr virus (EBV) infection. RASGRP1 is a T‐lymphocyte‐specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in RASGRP1 leading to the loss RASGRP1 expression was identified in two siblings who both developed a persistent EBV infection leading to Hodgkin lymphoma. RASGRP1‐deficient T cells exhibited defective MAPK activation and impaired proliferation that was restored by expression of wild‐type RASGRP1. Similar defects were observed in T cells from healthy individuals when RASGRP1 was downregulated. RASGRP1‐deficient T cells also exhibited decreased CD27‐dependent proliferation toward CD70‐expressing EBV‐transformed B cells, a crucial pathway required for expansion of antigen‐specific T cells during anti‐EBV immunity. Furthermore, RASGRP1‐deficient T cells failed to upregulate CTPS1, an important enzyme involved in DNA synthesis. These results show that RASGRP1 deficiency leads to susceptibility to EBV infection and demonstrate the key role of RASGRP1 at the crossroad of pathways required for the expansion of activated T lymphocytes. Synopsis RASGRP1 deficiency is characterized by a high susceptibility to develop Epstein‐Barr virus (EBV)‐driven B‐cell lymphoproliferative disorders such as B‐cell lymphoma like Hodgkin lymphoma. This is caused by defective expansion of activated T cells required for an efficient immune response to EBV. RASGRP1 is a critical factor of T‐cell proliferation including CD27‐, CD70‐ and CTPS1‐dependent pathways. RASGRP1 is required for expression of genes involved cell proliferation. This study emphasizes that T‐cell expansion is a critical step in immunity to EBV. Graphical Abstract RASGRP1 deficiency is characterized by a high susceptibility to develop Epstein‐Barr virus (EBV)‐driven B‐cell lymphoproliferative disorders such as B‐cell lymphoma like Hodgkin lymphoma. This is caused by defective expansion of activated T cells required for an efficient immune response to EBV.

Highly active antiretroviral therapy is unable to eliminate HIV infection, because the virus persists in latently infected CD4 + T cells—a so-called virus reservoir. Rafick-Pierre Sekaly and his colleagues have shown that central memory CD4 + T cells and transitional memory CD4 + T cells are the main cellular reservoirs for HIV, and they suggest a mechanism that ensures the stability of this reservoir of virus. HIV persists in a reservoir of latently infected CD4 + T cells in individuals treated with highly active antiretroviral therapy (HAART). Here we identify central memory (T CM ) and transitional memory (T TM ) CD4 + T cells as the major cellular reservoirs for HIV and find that viral persistence is ensured by two different mechanisms. HIV primarily persists in T CM cells in subjects showing reconstitution of the CD4 + compartment upon HAART. This reservoir is maintained through T cell survival and low-level antigen-driven proliferation and is slowly depleted with time. In contrast, proviral DNA is preferentially detected in T TM cells from aviremic individuals with low CD4 + counts and higher amounts of interleukin-7–mediated homeostatic proliferation, a mechanism that ensures the persistence of these cells. Our results suggest that viral eradication might be achieved through the combined use of strategic interventions targeting viral replication and, as in cancer, drugs that interfere with the self renewal and persistence of proliferating memory T cells.

Preservation of a functional keratinocyte stem cell pool is essential to ensure the long-term maintenance of epidermis integrity, through continuous physiological renewal and regeneration in case of injury. Protecting stem cells from inflammation and immune reactions is thus a critical issue that needs to be explored. Here, we show that the immature CD49f high precursor cell fraction from interfollicular epidermis keratinocytes, comprising stem cells and progenitors, is able to inhibit CD4 + T-cell proliferation. Of note, both the stem cell-enriched CD49f high /EGFR low subpopulation and the less immature CD49f high /EGFR high progenitors ensure this effect. Moreover, we show that HLA-G and PD-L1 immune checkpoints are overexpressed in CD49f high precursors, as compared to CD49f low differentiated keratinocytes. This potency may limit immune reactions against immature precursors including stem cells, and protect them from exacerbated inflammation. Further exploring this correlation between immuno-modulation and immaturity may open perspectives in allogenic cell therapies.

Induced pluripotent stem cell (iPSC)-derived mesenchymal stromal cells (iMSCs) offer a promising alternative to primary mesenchymal stromal cells (MSCs) and their derivatives, particularly extracellular vesicles (EVs), for use in advanced therapy medicinal products. In this study we evaluated the immunomodulatory and regenerative potential of iMSCs as well as iMSC-EVs, alongside primary human umbilical cord-derived mesenchymal stromal cells (hUCMSCs). Our findings demonstrate that iMSCs exhibit comparable abilities to hUCMSCs in regulating lymphocyte proliferation and inducing an anti-inflammatory phenotype in monocytes. We also observed decreased TNFα levels and increased IL-10 induction, indicating a potential mechanism for their immunomodulatory effects. Furthermore, iMSC-EVs also showed effective immunomodulation by inhibiting T cell proliferation and inducing macrophage polarization similar to their parental cells. Additionally, iMSC-EVs exhibited pro-regenerative potential akin to hUCMSC-EVs in in vitro scratch assays. Notably, priming iMSCs with pro-inflammatory cytokines significantly enhanced the immunomodulatory potential of iMSC-EVs. These results underscore the considerable promise of iMSCs and iMSCs-EVs as an alternate source for MSC-derived therapeutics, given their potent immunomodulatory and regenerative properties.

CD8 + T cells are major components of adaptive immunity and confer robust protective cellular immunity, which requires adequate T-cell numbers, targeted migration, and efficient T-cell proliferation. Altered CD8 + T-cell homeostasis and impaired proliferation result in dysfunctional immune response to infection or tumorigenesis. However, intrinsic factors controlling CD8 + T-cell homeostasis and immunity remain largely elusive. Here, we demonstrate the prominent role of Brd4 on CD8 + T cell homeostasis and immune response. By upregulating Myc and GLUT1 expression, Brd4 facilitates glucose uptake and energy production in mitochondria, subsequently supporting naïve CD8 + T-cell survival. Besides, Brd4 promotes the trafficking of naïve CD8 + T cells partially through maintaining the expression of homing receptors (CD62L and LFA-1). Furthermore, Brd4 is required for CD8 + T cell response to antigen stimulation, as Brd4 deficiency leads to a severe defect in clonal expansion and terminal differentiation by decreasing glycolysis. Importantly, as JQ1, a pan-BRD inhibitor, severely dampens CD8 + T-cell immune response, its usage as an anti-tumor agent or latency-reversing agent for human immunodeficiency virus type I (HIV-1) should be more cautious. Collectively, our study identifies a previously-unexpected role of Brd4 in the metabolic regulation of CD8 + T cell-mediated immune surveillance and also provides a potential immunomodulation target.

Background Blocking programmed death-1 (PD-1) is considered to be a promising strategy to improve T cell function, and this is being explored in many ongoing clinical trials. In fact, our knowledge about PD-1 is primarily based on the results of short-term experiments or observations, but how long-lasting PD-1 blockade can affect T cell function remains unclear. Methods We planned to use shRNA-based gene knockdown technology to mimic long-lasting PD-1 blockade. We constructed PD-1 steadily blocked chimeric antigen receptor modified T (CAR-T) cells, and with these cells we can clearly study the effects of PD-1 knockdown on T cell function. The anti-tumor function, proliferation ability and differentiation status of PD-1 silenced CAR-T cells were studied by in vitro and animal experiments. Results According to short-term in vitro results, it was reconfirmed that the resistance to programmed death-ligand 1 (PD-L1)-mediated immunosuppression could be enhanced by PD-1 blockade. However, better anti-tumor function was not presented by PD-1 blocked CAR-T cells in vitro or in vivo experiments. It was found that PD-1 knockdownmight impair the anti-tumor potential of CAR-T cells because it inhibited T cells’ proliferation activity. In addition, we observed that PD-1 blockade would accelerate T cells’ early differentiation and prevent effector T cells from differentiating into effect memory T cells, and this might be the reason for the limited proliferation of PD-1 silenced CAR-T cells. Conclusion These results suggest that PD-1 might play an important role in maintaining the proper proliferation and differentiation of T cells, and PD-1 silencing would impair T cells’ anti-tumor function by inhibiting their proliferation activity.

Cytomegalovirus (CMV) infection has a major impact on the T-cell pool, which is thought to be associated with ageing of the immune system. The effect on the T-cell pool has been interpreted as an effect of CMV on non-CMV specific T-cells. However, it remains unclear whether the effect of CMV could simply be explained by the presence of large, immunodominant, CMV-specific memory CD8 + T-cell populations. These have been suggested to establish through gradual accumulation of long-lived cells. However, little is known about their maintenance. We investigated the effect of CMV infection on T-cell dynamics in healthy older adults, and aimed to unravel the mechanisms of maintenance of large numbers of CMV-specific CD8 + T-cells. We studied the expression of senescence, proliferation, and apoptosis markers and quantified the in vivo dynamics of CMV-specific and other memory T-cell populations using in vivo deuterium labelling. Increased expression of late-stage differentiation markers by CD8 + T-cells of CMV+ versus CMV- individuals was not solely explained by the presence of large, immunodominant CMV-specific CD8 + T-cell populations. The lifespans of circulating CMV-specific CD8 + T-cells did not differ significantly from those of bulk memory CD8 + T-cells, and the lifespans of bulk memory CD8 + T-cells did not differ significantly between CMV- and CMV+ individuals. Memory CD4 + T-cells of CMV+ individuals showed increased expression of late-stage differentiation markers and decreased Ki-67 expression. Overall, the expression of senescence markers on T-cell populations correlated positively with their expected in vivo lifespan. Together, this work suggests that i) large, immunodominant CMV-specific CD8 + T-cell populations do not explain the phenotypical differences between CMV+ and CMV- individuals, ii) CMV infection hardly affects the dynamics of the T-cell pool, and iii) large numbers of CMV-specific CD8 + T-cells are not due to longer lifespans of these cells.

Lung adenocarcinoma (LUAD), the major lung cancer histotype, represents 40% lung cancers. Currently, outcomes are remarkably different in LUAD patients with similar AJCC/UICC-TNM features. T cell proliferation-related regulator genes (TPRGs) relate to the proliferation, activity and function of T cells and tumor progression. The values of TPRGs in classifying LUAD patients and predicting outcomes remain unknown. Gene expression profile and corresponding clinical data were downloaded from TCGA and the GEO databases. We systematically analyzed the expression profile characteristics of 35 TPRGs in LUAD patients and investigated the differences in overall survival (OS), biology pathway, immunity and somatic mutation between different TPRGs-related subtypes. Subsequently, we constructed a TPRGs-related risk model in TCGA cohort to quantify risk scores using LASSO cox regression analysis and then validated this risk model in two GEO cohorts. LUAD patients were divided into high- and low-risk subtypes according to the median risk score. We systematically compared the biology pathway, immunity, somatic mutation and drug susceptibility between the two risk subtypes. Finally, we validate biological functions of two TPRGs-encoded proteins (DCLRE1B and HOMER1) in LUAD cells A549. We identified different TPRGs-related subtypes (including cluster 1/cluster A and its counterpart cluster 2/cluster B). Compared to the cluster 1/cluster A subtype, cluster 2/cluster B subtype tended to have a prominent survival advantage with an immunosuppressive microenvironment and a higher somatic mutation frequency. Then, we constructed a TPRGs-related 6-gene risk model. The high-risk subtype characterized by higher somatic mutation frequency and lower immunotherapy response had a worse prognosis. This risk model was an independent prognostic factor and showed to be reliable and accurate for LUAD classification. Furthermore, subtypes with different risk scores were significantly associated with drug sensitivity. DCLRE1B and HOMER1 suppressed cell proliferation, migration and invasion in LUAD cells A549, which was in line with their prognostic values. We construed a novel stratification model of LUAD based on TPRGs, which can accurately and reliably predict the prognosis and might be used as a predictive tool for LUAD patients.

Klebsiella pneumoniae ( Kp ) is responsible for a wide range of infections, including pneumonia, sepsis, and urinary tract infections. However, the treatment options are limited due to the continuous evolution of drug-resistant and hypervirulent variants. It is crucial to investigate the mechanisms behind the high mortality rate of hypervirulent Kp (hv Kp ) strains to develop new strategies for preventing hv Kp from evading the host’s defenses and improving treatment effectiveness for these fatal infections. In this study, we used a hv Kp -induced mouse bacteremia model and performed single-cell RNA sequencing to investigate the effects of hv Kp infection. Our findings demonstrated that hv Kp infection led to a decrease in lymphocytes (lymphopenia), attributed to impaired proliferation and apoptosis. The infiltration of myeloid-derived suppressor cells (MDSCs) in the infected lungs was confirmed to suppress T cell proliferation, leading to lymphopenia. We further identified that hv Kp promotes tryptophan metabolism in infected lungs, enhancing the immunosuppressive activity of MDSCs by inducing the production of the enzyme IDO1. Our ex vivo inhibition experiment revealed that L-kynurenine, a product of tryptophan metabolism, inhibits T-cell proliferation and induces T-cell apoptosis, further suppressing T-cell mediated responses against bacteria. Importantly, when we knocked out the Ido1 gene or inhibited IDO1 expression using a specific inhibitor 1-MT in mice, we observed a significant enhancement in T-cell mediated responses against hv Kp . These findings highlight the crucial role of MDSCs in hv Kp -induced bacteremia and suggest a promising immunotherapeutic approach by inhibiting IDO1 production to combat infectious diseases.