Loss of tonic T-cell receptor signals alters the generation but not the persistence of CD8+ memory T cells

Abstract

IntroductionProtection against recurrent infections resulting from the same pathogen is a hallmark of adaptive immunity. After acute infection by an intracellular pathogen, naive CD8 ϩ T cells expressing epitope-specific T-cell receptors (TCRs) are activated. The effector phase of the response is short, with a rapid expansion of antigenspecific T cells and pathogen clearance. The expanded effector cells undergo a contraction phase, while approximately 5% to 10% of antigen-specific cells are maintained to establish a memory pool and provide long-term protection from reinfection by the same pathogen. [1][2][3] In the early stages of the effector response to acute lymphocytic choriomeningitis virus (LCMV) infection, activated CD8 ϩ cells differentiate into 2 subsets with distinct fates. These populations can be phenotypically identified by cell-surface expression of killer cell lectin-like receptor G1 (KLRG-1) and the receptor for interleukin-7 (IL-7R). 4 Short-lived effector cells (SLECs) express high levels of KLRG-1 and the transcription factors Blimp-1 and T-bet, and decreased levels of IL-7R. [5][6][7][8] SLECs are dependent on signals from the environment, including TCR signals, inflammatory cytokines such as IL-12 and IFN␥, and common ␥ chain cytokine signaling from IL-2 and IL-15. 4,9 Conversely, memory precursor (MP) cells express low levels of KLRG-1 and higher levels of IL-7R␣, CXCR3, and CD27. 4,10,11 While these cells possess effector function, they also have the potential to further differentiate into long-lived memory T cells after the resolution of infection. The molecular nature of the proximal signals involved in the SLEC/MP cell-fate decision and those required for normal homeostasis of these populations have not been extensively studied.Previous studies have shown that IL-15-and IL-7-generated signals are required for memory T-cell homeostasis. [12][13][14][15] Depending on the experimental system and the characteristics used to define the memory population, TCR signals have been shown to be required or dispensable. For example, H-2D b -restricted, malespecific (H-Y TCR-transgenic) memory CD8 ϩ T cells require expression of either H-2D b or H-2D d for survival. 16 The absence of all major histocompatibility complex (MHC) class I expression leads to the disappearance of the cells, suggesting that a tonic MHC-TCR signal is required. In addition, CD8 ϩ CD44 hi cells do not persist in mice after gene deletion of the TCR␣ chain. 17 In contrast, polyclonal CD8 ϩ T-cell populations containing memory CD8 ϩ T cells generated by viral infection persist indefinitely when transferred into MHC class I-deficient mice. 18 CD44 hi cells and TCR-transgenic memory T cells persist long term, even when the expression of the src family tyrosine kinase Lck or of TCR itself is substantially decreased by a bitransgenic tetracycline regulatory system. [19][20][21] An obstacle to characterizing the requirements for memory population generation and persistence is the heterogeneity of definitions for memory CD8 ϩ T cells o...

T-cell receptor signals direct the composition and function of the memory CD8+ T-cell pool

“…48 While these data suggest a late role for SLP-76 signals in memory differentiation they do not preclude an early role for SLP-76 in programming differentiation patterns. Taken together, these data suggest that the kinetics of the transition of the memory pool to a more mature and Tcm-dominant phenotype is influenced by TCR signals and that strong TCR signals are required for terminal differentiation.…”

Regulatory T Cells Require TCR Signaling for Their Suppressive Function

“…Since SLP-76 cKO naïve and effector T cells display a survival defect (35, 36), we tested if a lack of fitness was responsible for the functional defect observed in SLP-76 cKO Tregs. The number of Tregs recovered from the suppression assays was significantly decreased in cultures with SLP-76 cKO compared to SLP-76 cHet Tregs (Fig.…”

Differential Regulation of Primary and Memory CD8 T Cell Immune Responses by Diacylglycerol Kinases

“…Engagement of CD8 + T cells with antigen presenting cells through the interaction between viral specific TCRs and viral peptide:MHC-I complex is critical for the initiation of CD8 + T cell mediated anti-viral immunity. The signal strength from viral specific TCRs can influence the effector and memory CD8 + T cell differentiation, maintenance, and activation (3–5, 7, 50). We demonstrate that both DGKα and ζ are important regulators for CD8 + T cell-mediated anti-viral immune responses and that DGK activity plays differential roles in primary and memory CD8 + T cell responses.…”