CD8 T cells inhibit cytotoxic CD4 T cell responses during chronic viral infection 4739

Abstract Description Although CD4 T cells are traditionally known as helper cells, a subset of antiviral CD4 T cells express cytotoxic markers and can directly kill MHC II+ target cells in vivo. It is becoming increasingly evident that these cytotoxic CD4 T cells (CD4 CTLs) play an important role in combatting various chronic viral infections and cancers, however the mechanisms regulating their formation and maintenance remain unclear. Upon chronic LCMV infection we demonstrate that CD4 T cells preferentially differentiate into perforin-expressing cytotoxic Th1 cells in mice lacking CD8 T cells (beta-2-microglobulin (B2m-/-) or CD8-/- mice) as compared to wildtype mice. Although CD4 CTLs progressively lose their cytotoxic function as a mechanism of CD4 T cell exhaustion, B2m-/- CD4 CTLs had higher in vivo cytotoxic capacity and expressed less PD1 on a per cell basis than WT CD4 CTLs. Strikingly, CD4 CTL numbers and CD4-mediated in vivo killing was maintained as virus persisted in B2m-/- mice, but waned in WT mice. Similar results were observed in CD8-/- mice. Thus, CD8 T cells suppress cytotoxic CD4 T cell formation and maintenance during chronic viral infection. Ongoing work will define the mechanisms by which cytotoxic CD4 T cells are primed in the absence of CD8 T cells. Ultimately, our study will reveal novel insights into the mechanisms that regulate antiviral CD4 CTL responses. Funding Sources This work was funded by a Showalter Trust Foundation award, the Indiana CTSI and funds from IUSCCC and IU CCEH. Topic Categories Viral Immunology (VIR)