Transplant mice with acute viral infection develop functionally distinct antigen-specific PD-1- and PD-1+ CXCR5+CD8+...

We investigated the development, antigen specificity, and effector functions of PD-1- and PD-1+ CXCR5+CD8+ T-cell subsets in transplant mice with acute murine cytomegalovirus (MCMV) infection. MCMV-primed (MCMV-Tet+) or alloprimed (MCMV-Tet-) CD8+ T cells from C57BL/6 mice were flow-sorted and adoptively transferred into MCMV-infected CD8 knockout transplant recipients. Alloantibody titer, quantities of primed germinal center (GC) B cells, anti-MCMV antibody titer, and MCMV viral titer were assessed on day 14 posttransplant. Following adoptive transfer (AT), alloprimed PD-1- (but not PD-1+) CXCR5+CD8+ T cells mediated suppression of alloantibody (1.8-fold) and reduced the quantity of alloprimed (alloTet+) GC B cells (2.4-fold) and CD4+ TFH cells (2.8-fold) but did not impact anti-MCMV antibody levels, the quantity of MCMV-primed GC B cells or CD4+ TFH cells, or MCMV viral titer. Conversely, AT of MCMV-primed (MCMV-Tet+) CXCR5+PD-1-CD8+ T cells into MCMV-infected transplant mice suppressed anti-MCMV antibody (1.7-fold) and reduced the quantity of MCMV-primed GC B cells (3.3-fold) and MCMV-Tet+ CD4+ TFH cells (2.5-fold) but did not impact alloantibody levels, the quantity of alloprimed GC B cells or CD4+ TFH cells, nor MCMV viral titer. Antibody suppression by antigen-specific CXCR5+PD-1-CD8+ T cells is associated with cytotoxic killing of antigen-primed GC B cells in vitro and reduction of antigen-primed GC B-cell quantity in vivo. In contrast, AT of MCMV-primed CXCR5+PD-1+CD8+ T cells reduced MCMV viral titer without influencing anti-MCMV antibody or alloantibody levels. These data indicate that PD-1- and PD-1+ subsets of CXCR5+CD8+ T cells, which emerge acutely after viral infection or transplant, mediate distinct antigen-specific effector functions.