Interruption with TNFα/TNFR1 function impairs host immune response against cutaneous vaccinia virus infection (52.8)

Abstract

One strategy adopted by vaccinia virus (VV) to evade the host immune system is to encode homologs of TNF receptors (TNFR) that block TNFα function. The response to VV skin infection under conditions of TNFα deficiency, however, has not been reported. We found that TNFR1-/- developed larger skin lesions with higher virus levels after VV scarification. Following their recovery, these TNFR1-/- mice were fully protected against lethal VV intranasal challenge, suggesting their effective memory immune response. A functional systemic immune response of TNFR1-/- mice was further demonstrated by enhanced production of VV-specific IFNγ and CD8+ T cells in spleens and draining lymph nodes as well as efficient T cell skin homing. Interestingly, bone marrow (BM) reconstitution studies using WT BM →TNFR1-/- mice, but not TNFR1-/- BM → WT mice, reproduced the original results seen in TNFR1-/- mice, indicating that TNFR1 deficiency in resident skin cells, rather than hematopoietic cells, accounts for the impaired cutaneous immune response. Similar phenotype was also found in in TNFα-/- mice following VV scarification while both WT BM→ TNFα-/- mice and TNFα-/-BM →WT mice developed significantly larger skin lesions with higher virus counts than the control chimeric mice.Therefore, while the target of TNFα action is restricted to skin stromal components, the source of TNFα produced in response to VV infection would appear to include both hematopoietic cells and radioresistant skin elements.