The CD8 T cell response to vaccinia virus exhibits site-dependent heterogeneity of functional responses

CD8 T cell responses to vaccinia virus (VV) and a virus-encoded ovalbumin peptide (OVAP) epitope were examined using adoptively transferred OT-I T cells. The results demonstrate that upon intra-peritoneal challenge with ovalbumin-expressing VV (VV-OVAP), OT-I T cell proliferation occurs initially in lymph nodes and spleens followed by migration of the divided cells to the peritoneal cavity. Massive clonal expansion occurs in response to both the virus and the virus-encoded ovalbumin (OVA) epitope, as demonstrated using low numbers of adoptively transferred cells, and the responding OT-I cells display marked site-dependent functional heterogeneity with respect to IFN-γ and tumor necrosis factor-α (TNF-α) production and granzyme B expression. OT-I cells responding to VV-OVAP develop the capacity to produce IFN-γ in response to antigen as they proliferate and differentiate. In marked contrast, naive OT-I cells rapidly produce TNF-α upon antigen recognition, and this capacity declines as the cells proliferate in response to the virus, suggesting that this potent inflammatory cytokine may be important primarily during initiation of the response. At the peak of clonal expansion, a large fraction (30-60%) of the OT-I cells responding to the virus express high IL-7Rα levels, and the majority of these cells is subsequently lost. While high IL-7Rα expression may be necessary for a CD8 T cell to transition to memory, it is clearly not sufficient. Thus, OT-I cells responding to VV infection exhibit a high degree of heterogeneity within the responding population that differs depending on their anatomical location, despite the specificity and affinity of the TCR being identical on all of the cells.