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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nuclear components. Circulating immune complexes of chromatin and autoantibodies deposit in various tissues leading to inflammation and tissue damage. It has been well documented that autoimmunity in SLE depends on autoreactive T cells. In this review, we summarize the literature that addresses the roles of T cell signaling, and Th17 and regulatory T cells (Tregs) in the development of SLE. T cell receptor (TCR) signaling appears to be aberrant in T cells of patients with SLE. In particular, defects in the TCRζ chain, Syk kinase, and calcium signaling molecules have been associated with SLE, which leads to hyperresponsive autoreactive T cells. Furthermore, in patients with SLE increased numbers of autoreactive Th17 cells have been documented, and Th17 cells appear to be responsible for tissue inflammation and damage. In addition, reduced numbers of Tregs as well as Tregs with an impaired regulatory function have been associated with SLE. The altered balance between the number of Tregs and Th17 cells in SLE may result from changes in the cytokine milieu that favors the development of Th17 cells over Tregs.

High surface expression of programmed death 1 (PD-1) is associated with T-cell exhaustion; however, the relationship between PD-1 expression and T-cell dysfunction has not been delineated. We developed a model to study PD-1 signaling in primary human T cells to study how PD-1 expression affected T-cell function. By determining the number of T-cell receptor/peptide-MHC complexes needed to initiate a Ca ²⁺ flux, we found that PD-1 ligation dramatically shifts the dose–response curve, making T cells much less sensitive to T-cell receptor–generated signals. Importantly, other T-cell functions were differentially sensitive to PD-1 expression. We observed that high levels of PD-1 expression were required to inhibit macrophage inflammatory protein 1 beta production, lower levels were required to block cytotoxicity and IFN-γ production, and very low levels of PD-1 expression could inhibit TNF-α and IL-2 production as well as T-cell expansion. These findings provide insight into the role of PD-1 expression in enforcing T-cell exhaustion and the therapeutic potential of PD-1 blockade.

CD4(+)CD25(high)Foxp3(+) regulatory T cells (Tregs) can suppress other immune cells and, thus, are critical mediators of peripheral self-tolerance. On the one hand, Tregs avert autoimmune disease and allergies. On the other hand, Tregs can prevent immune reactions against tumors and pathogens. Despite the importance of Tregs, the molecular mechanisms of suppression remain incompletely understood and controversial. Proliferation and cytokine production of CD4(+)CD25(-) conventional T cells (Tcons) can be inhibited directly by Tregs. In addition, Tregs can indirectly suppress Tcon activation via inhibition of the stimulatory capacity of antigen presenting cells. Direct suppression of Tcons by Tregs can involve immunosuppressive soluble factors or cell contact. Different mechanisms of suppression have been described, so far with no consensus on one universal mechanism. Controversies might be explained by the fact that different mechanisms may operate depending on the site of the immune reaction, on the type and activation state of the suppressed target cell as well as on the Treg activation status. Further, inhibition of T cell effector function can occur independently of suppression of proliferation. In this review, we summarize the described molecular mechanisms of suppression with a particular focus on suppression of Tcons and rapid suppression of T cell receptor-induced calcium (Ca(2+)), NFAT, and NF-κB signaling in Tcons by Tregs.

Despite decades of research, mechanisms controlling T cell activation remain only partially understood, which hampers T cell-based immune cancer therapies. Here, we performed a genome-wide CRISPR screen to search for genes that regulate T cell activation. Our screen confirmed many of the known regulators in proximal T cell receptor signaling and, importantly, also uncovered a previously uncharacterized regulator, FAM49B (family with sequence similarity 49 member B). FAM49B deficiency led to hyperactivation of Jurkat T cells following T cell receptor stimulation, as indicated by enhancement of CD69 induction, PAK phosphorylation, and actin assembly. FAM49B directly interacted with the active form of the small GTPase Rac, and genetic disruption of the FAM49B–Rac interaction compromised FAM49B function. Thus, FAM49B inhibits T cell activation by repressing Rac activity and modulating cytoskeleton reorganization.

Persistent T cell antigen receptor (TCR) signaling by CD8 T cells is a feature of cancer and chronic infections and results in the sustained expression of, and signaling by, inhibitory receptors, which ultimately impair cytotoxic activity via poorly characterized mechanisms. We have previously determined that the LPA5 GPCR expressed by CD8 T cells, upon engaging the lysophosphatidic acid (LPA) bioactive serum lipid, functions as an inhibitory receptor able to negatively regulate TCR signaling. Notably, the levels of LPA and autotaxin (ATX), the phospholipase D enzyme that produces LPA, are often increased in chronic inflammatory disorders such as chronic infections, autoimmune diseases, obesity, and cancer. In this report, we demonstrate that LPA engagement selectively by LPA5 on human and mouse CD8 T cells leads to the inhibition of several early TCR signaling events including intracellular calcium mobilization and ERK activation. We further show that, as a consequence of LPA5 suppression of TCR signaling, the exocytosis of perforin-containing granules is significantly impaired and reflected by repressed in vitro and in vivo CD8 T cell cytolytic activity. Thus, these data not only document LPA5 as a novel inhibitory receptor but also determine the molecular and biochemical mechanisms by which a naturally occurring serum lipid that is elevated under settings of chronic inflammation signals to suppress CD8 T cell killing activity in both human and murine cells. As diverse tumors have repeatedly been shown to aberrantly produce LPA that acts in an autocrine manner to promote tumorigenesis, our findings further implicate LPA in activating a novel inhibitory receptor whose signaling may be therapeutically silenced to promote CD8 T cell immunity.

T‐cell receptor (TCR) ligation‐mediated protein phosphorylation regulates the activation, cellular responses, and fates of T cells. Here, we used time‐resolved high‐resolution phosphoproteomics to identify, quantify, and characterize the phosphorylation dynamics of thousands of phosphorylation sites in primary T cells during the first 10 min after TCR stimulation. Bioinformatic analysis of the data revealed a coherent orchestration of biological processes underlying T‐cell activation. In particular, functional modules associated with cytoskeletal remodeling, transcription, translation, and metabolic processes were mobilized within seconds after TCR engagement. Among proteins whose phosphorylation was regulated by TCR stimulation, we demonstrated, using a fast‐track gene inactivation approach in primary lymphocytes, that the ITSN2 adaptor protein regulated T‐cell effector functions. This resource, called LymphoAtlas, represents an integrated pipeline to further decipher the organization of the signaling network encoding T‐cell activation. LymphoAtlas is accessible to the community at: https://bmm-lab.github.io/LymphoAtlas . Synopsis The study presents LymphoAtlas, a phosphoproteomic dataset enabling the identification and visualization of phosphorylation dynamics during the first 10 min after TCR stimulation of primary mouse T cells. LymphoAtlas is a time‐resolved phosphoproteomic analysis in primary T cells. LymphoAtlas reveals coherent and dynamic orchestration of biological processes underlying T‐cell activation. LymphoAtlas reveals novel effectors involved in the TCR signaling pathway. Graphical Abstract The study presents LymphoAtlas, a phosphoproteomic dataset enabling the identification and visualization of phosphorylation dynamics during the first 10 min after TCR stimulation of primary mouse T cells.

The role of Bruton’s tyrosine kinase (BTK) in BCR signaling is well defined, and BTK is involved in B-cell development, differentiation, and malignancies. However, the expression of Btk in T cells and its role in T-cell function remain largely unknown. Here, we unexpectedly found high expression and activation of BTK in T cells. Deficiencies in BTK resulted in the impaired activation and proliferation of autoreactive T cells and ameliorated bone marrow failure (BMF) in aplastic anemia. Mechanistically, BTK is activated after TCR engagement and then phosphorylates PLCγ1, thus promoting T-cell activation. Treatment with acalabrutinib, a selective BTK inhibitor, decreased T-cell proliferation and ameliorated BMF in mice with aplastic anemia. Our results demonstrate an unexpected role of BTK in optimal T-cell activation and in the pathogenesis of autoimmune aplastic anemia, providing insights into the molecular regulation of T-cell activation and the pathogenesis of T-cell-mediated autoimmune disease.

Naïve CD4⁺ T cells experience weak T cell receptor (TCR) signals induced by self-peptides presented by MHC II. To investigate how these “basal” TCR signals influence responses to agonist TCR ligand stimulation, we analyzed naïve CD4⁺ cells expressing varying amounts of CD5, Ly6C, and Nur77-GFP, markers that reflect the strength of basal TCR signaling. Phenotypic analyses indicate that the broadest range of basal TCR signal strength can be visualized by a combination of Nur77-GFP and Ly6C. A range of basal TCR signaling is detectable even in populations that express identical TCRs. Whereas moderate basal TCR signal strength correlates with higher IL-2 secretion at early time points following TCR stimulation, weak basal TCR signaling correlated with higher IL-2 secretion at later time points. We identify a population of Nur77-GFPHI Ly6C⁻ cells that could not be reliably marked by either of CD5, Ly6C, or Nur77-GFP alone. These cells experience the strongest basal TCR signaling, consistently produce less IL-2, and express PD-1 and markers associated with anergy, such as Grail and Cbl-b. We propose that adaptation to the strength of basal TCR signaling drives the phenotypic and functional heterogeneity of naïve CD4⁺ cells.

It has been shown that the transgene insertional mutations TM1 and TM2 constitute a genetic trait controlling thymocyte development. Here we conducted a detailed analysis of the impact of TM1 and TM2 double mutation on thymocyte development. We found that the hemizygous TM1 and TM2 double transgenic mice possessed much smaller thymi. Flow cytometric analysis revealed a severe blockage of T‐cell development at the transition from DN3 to DN4 stage and pre‐T‐cell receptor (pre‐TCR)/TCR signaling appeared to be impaired. We could not identify any known gene that was implicated in a similar function in the chromosomal regions 7E–F1 and 11B5–C, where TM1 and TM2 mutations were mapped to respectively. Thus, TM1 and TM2 mutations represent two novel alleles that define a genetic trait controlling DN3 thymocyte development, possibly through modulating the signals downstream of the pre‐TCR.

Immature T cells undergo a process of positive selection in the thymus when their new T cell receptor (TCR) engages and signals in response to self-peptides. As the T cell matures, a slew of negative regulatory molecules, including the inhibitory surface glycoprotein CD5, are up-regulated in proportion to the strength of the self-peptide signal. Together these regulators dampen TCR-proximal signaling and help avoid any subsequent peripheral activation of T cells by self-peptides. Paradoxically, antigen-specific T cells initially expressing more CD5 (CD5hi) have been found to better persist as effector/memory cells after a peripheral challenge. The molecular mechanisms underlying such a duality in CD5 function is not clear. We found that CD5 alters the basal activity of the NF-κB signaling in resting peripheral T cells. When CD5 was conditionally ablated, T cells were unable to maintain higher expression of the cytoplasmic NF-κB inhibitor IκBα. Consistent with this, resting CD5hi T cells expressed more of the NF-κB p65 protein than CD5lo cells, without significant increases in transcript levels, in the absence of TCR signals. This posttranslationally stabilized cellular NF-κB depot potentially confers a survival advantage to CD5hi T cells over CD5lo ones. Taken together, these data suggest a two-step model whereby the strength of self-peptide–induced TCR signal lead to the up-regulation of CD5, which subsequently maintains a proportional reserve of NF-κB in peripheral T cells poised for responding to agonistic antigen-driven T cell activation.