Resident T lymphocytes (T RM ) protect tissues during pathogen reexposure. Although T RM phenotype and restricted migratory pattern are established, we have a limited understanding of their response kinetics, stability, and turnover during reinfections. Such characterizations have been restricted by the absence of in vivo fate-mapping systems. We generated two mouse models, one to stably mark CD103 + T cells (a marker of T RM cells) and the other to specifically deplete CD103 − T cells. Using these models, we observed that intestinal CD103 + T cells became activated during viral or bacterial reinfection, remained organ-confined, and retained their original phenotype but failed to reexpand. Instead, the population was largely rejuvenated by CD103 + T cells formed de novo during reinfections. This pattern remained unchanged upon deletion of antigen-specific circulating T cells, indicating that the lack of expansion was not due to competition with circulating subsets. Thus, although intestinal CD103 + resident T cells survived long term without antigen, they lacked the ability of classical memory T cells to reexpand. This indicated that CD103 + T cell populations could not autonomously maintain themselves. Instead, their numbers were sustained during reinfection via de novo formation from CD103 − precursors. Moreover, in contrast to CD103 - cells, which require antigen plus inflammation for their activation, CD103 + T RM became fully activated follwing exposure to inflammation alone. Together, our data indicate that primary CD103 + resident memory T cells lack secondary expansion potential and require CD103 − precursors for their long-term maintenance.
Mature T cells must discriminate between brief interactions with self-peptides and prolonged binding to agonists. The kinetic proofreading model posits that certain T-cell antigen receptor signaling nodes serve as molecular timers to facilitate such discrimination. However, the physiological significance of this regulatory mechanism and the pathological consequences of disrupting it are unknown. Here we report that accelerating the normally slow phosphorylation of the linker for activation of T cells (LAT) residue Y136 by introducing an adjacent Gly135Asp alteration (LATG135D) disrupts ligand discrimination in vivo. The enhanced self-reactivity of LATG135D T cells triggers excessive thymic negative selection and promotes T-cell anergy. During Listeria infection, LATG135D T cells expand more than wild-type counterparts in response to very weak stimuli but display an imbalance between effector and memory responses. Moreover, despite their enhanced engagement of central and peripheral tolerance mechanisms, mice bearing LATG135D show features associated with autoimmunity and immunopathology. Our data reveal the importance of kinetic proofreading in balancing tolerance and immunity.
Prolonged antigen exposure in chronic viral infections reduces the effector capacity of cytotoxic T cells - a phenomenon known as T cell exhaustion. High viral titer, strong TCR stimulation, and high antigen concentrations associated with strong inflammatory signals are known factors that promote the development of T cell exhaustion. A largely unexplored factor has been the influence of the microbiome on the development of T cell exhaustion. We report that T cell exhaustion progresses independently of the presence or absence of a bacterial microbiome in chronic lymphocytic choriomeningitis virus (LCMV) infections. Virus-specific CD8 T cells in germ-free mice showed high expression of the inhibitory receptor PD-1 and decreased cytokine production. Moreover, their global gene expression patterns, as determined by single-cell sequencing, were similar to those of cells in specific pathogen-free mice. In stark contrast to the phenotypic similarities, the absence of the microbiome delayed the partial viral control typically seen in chronic LCMV infections. Thus, our study demonstrates that the microbiome is dispensable for the induction of T cell exhaustion but critical for effector T cell function in chronic LCMV infections.
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