Künzli, M. | Search bioRxiv

bioRxiv2020

Opposing effects of T cell receptor signal strength on CD4 T cells responding to acute versus chronic viral infection

A hallmark of the adaptive immune response is the ability of CD4 T cells to differentiate into a variety of pathogen appropriate and specialized effector subsets. A long-standing question in CD4 T cell biology is whether the strength of TCR signals can instruct one Th cell fate over another. The contribution of TCR signal strength to the development of Th1 and T follicular helper (Tfh) cells has been particularly difficult to resolve, with conflicting results reported in a variety of models. Although cumulative TCR signal strength can be modulated by the infection specific environment, whether or not TCR signal strength plays a dominant role in Th1 versus Tfh cell fate decisions across distinct infectious contexts is not known. Here we characterized the differentiation of CD4 TCR transgenic T cells responding to a panel of recombinant wild type or altered peptide ligand lymphocytic choriomeningitis viruses (LCMV) derived from acute and chronic parental strains. We found that while TCR signal strength positively regulates T cell expansion in both infection settings, it exerts opposite and hierarchical effects on the balance of Th1 and Tfh cells generated in response to acute versus persistent infection. The observation that weakly activated T cells, which comprise up to fifty percent of an endogenous CD4 T cell response, support the development of Th1 effectors highlights the possibility that they may resist functional inactivation during chronic infection. We anticipate that the panel of variant ligands and recombinant viruses described herein will be a valuable tool for immunologists investigating a wide range of CD4 T cell responses. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/236497v2_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1fdb592org.highwire.dtl.DTLVardef@19bc5e3org.highwire.dtl.DTLVardef@1dcf03forg.highwire.dtl.DTLVardef@20f27f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIdentification of a wide panel of altered peptide ligands for the LCMV-derived GP61 peptide C_LIO_LIGeneration of LCMV variant strains to examine the impact of TCR signal strength on CD4 T cells responding during acute and chronic viral infection C_LIO_LIThe relationship between TCR signal strength and Th1 differentiation shifts according to the infection context: TCR signal strength correlates positively with Th1 generation during acute infection but negatively during chronic infection. C_LI

immunology↗

bioRxiv2019

Persistence and plasticity of T follicular memory cells

CD4 memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (TCM) cells, while the existence and functional significance of T follicular helper (TFH) memory cells is controversial. Here we show that TFH memory cells are highly susceptible to NAD induced cell death (NICD) during isolation from tissues, leading to their under-representation in prior studies. NICD blockade reveals the persistence of abundant TFH memory cells, with high expression of hallmark TFH markers, that persist to at least 400 days after infection, by which time TCM cells are no longer found. Using single cell RNA-seq we demonstrate that TFH memory cells are transcriptionally distinct from TCM cells, maintain stemness and self-renewal gene expression, and, in contrast to TCM cells, are multipotent following recall. Surprisingly, TFH memory cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR, HIF-1 and cAMP regulated genes. Late disruption of glycolysis/ICOS signaling leads to TFH memory cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of memory TFH and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct memory T cell subsets and establish TFH memory cells as an attractive target for the induction of long-lived adaptive immunity.\n\nHIGHLIGHTSO_LICell death during isolation from the tissue prevents the full recovery of TFH memory cells\nC_LIO_LITFH memory cells are transcriptionally distinct from TCM cells and maintain a broader recall capacity\nC_LIO_LITFH memory cells are maintained in the absence of antigen but require ICOS signaling and glycolysis\nC_LIO_LITFH memory cells support late phase antibody production by splenic plasma cells\nC_LI

immunology↗