Homeostatic Division Is Not Necessary for Antigen-Specific CD4+ Memory T Cell Persistence

Abstract

CD4+ memory T cells are generated in response to infection or vaccination, provide protection to the host against re-infection, and persist through a combination of enhanced survival and slow homeostatic turnover. We used timed deletion of the TCR-signaling adaptor molecule SH2-domain-containing phosphoprotein of 76 kDa (SLP-76) with MHC:peptide tetramers to study the requirements for tonic TCR signals in the maintenance of polyclonal antigen-specific CD4+ memory T cells. SLP-76 deficient I-Ab:GP61 cells are unable to rapidly generate effector cytokine or proliferate in response to secondary infection. In mice infected with lymphocytic choriomeningitis virus (LCMV) or Listeria monocytogenes expressing the LCMV GP61-80 peptide, SLP-76 deficient I-Ab:GP61+ cells exhibit reduced division, similar to that seen in in vitro generated CD44hi and endogenous CD4+CD44hi cells. Competitive bone marrow chimera experiments demonstrated that the decrease in homeostatic turnover in the absence of SLP-76 is a cell intrinsic process. Surprisingly, despite the reduction in turnover, I-Ab:GP61+ antigen-specific memory cells persist in normal numbers for more than 30 weeks post LCMV infection in the absence of SLP-76. These data suggest the independent maintenance of a population of antigen-specific CD4+ memory T cells in the absence of SLP-76 and normal levels of homeostatic division.

B cells are sufficient to prime the dominant CD4+ Tfh response to Plasmodium infection

“…1 B). Furthermore, in LCMV, the numbers of GP66 + cells contracted with viral clearance and then stabilized to maintain a population of long-lived memory cells, as previously described (Corbo-Rodgers et al, 2012;Hondowicz et al, 2018;Matloubian et al, 1994).…”

Dynamic Post-Transcriptional Events Governing CD8+ T Cell Homeostasis and Effector Function

“…When naive CD4 + T cells from uninfected mice were immediately fixed upon isolation, low-level phosphorylation of S6 protein was observed, pointing to mTORC-1 activity and, thus, basal translation of mTOR targets during homeostasis [50]. In memory T cells, the constitutively active kinases lymphocyte-specific protein tyrosine kinase (Lck), zeta-chain-associated protein kinase (ZAP)-70, and the adapter protein signal-transducing adaptor protein SLP-76 confer tonic signals through the T cell receptor (TCR) [51][52][53][54]. These signals are required to maintain functionally competent naïve and memory T cells [52][53][54], and to reduce the threshold for T cell activation.…”

“…In memory T cells, the constitutively active kinases lymphocyte-specific protein tyrosine kinase (Lck), zeta-chain-associated protein kinase (ZAP)-70, and the adapter protein signal-transducing adaptor protein SLP-76 confer tonic signals through the T cell receptor (TCR) [51][52][53][54]. These signals are required to maintain functionally competent naïve and memory T cells [52][53][54], and to reduce the threshold for T cell activation. In addition, the common γ-chain binding cytokines IL-7 and IL-15 ensures memory T cell survival and homeostatic proliferation [55,56], and propagates the permissive epigenetic signature of human memory T cells to daughter cells [57].…”