Effector CD4(+) T cells can convert to a CD8(+), MHCII-restricted T cell lineage

Abstract CD4+ and CD8+ T cells are conventionally considered as separate lineages characterized by distinct surface markers, function and MHC restriction. However, CD4+ T cells have a recently-appreciated capacity to acquire CD8+ T cell-like characteristics upon TCR-mediated activation. We have identified a novel, CD4+ T cell-derived effector population in mice that is CD4−CD8αβ+ and MHCII-restricted. These cells express a unique lineage-intermediate transcriptional program (ThPOKlo-int Runx3hi-int), upregulate granzyme B/IFN-γ expression and exhibit antigen-specific cytotoxicity. Following acute infection with LCMV Armstrong in wild-type mice or with Listeria monocytogenes in MHCII-restricted, TCR-transgenic mice, we have used CD4+ T cell lineage tracing, MHCII tetramer staining and TCR repertoire sequencing techniques to demonstrate that ex-CD4+ T cell responses can be induced in vivo and originate from bona fide CD4+ T cells. We also report ex-CD4+-like T cells in human HIV patients that are CD8+ and exhibit MHCII-blockable antiviral activity. This population is diminished in elite controller patients upon loss of virus control, indicating that it may contribute to protection against HIV. Finally, we have generated preliminary evidence that ex-CD4+ T cell generation is controlled by an autophagy-related mechanism. CD4+ T cell-specific deficiency in either of the autophagy regulators Vps34 or Atg7 results in dramatic loss of CD4 expression upon antigen stimulation, concomitant with skewing towards the CD8+ transcriptional program in Vps34-deficient cells. We propose that the ex-CD4+ T cell lineage dramatically extends the paradigm of αβ T cell lineage plasticity and may indicate new antiviral vaccine strategies.