Tegument-specific, virus-reactive CD4 T cells localize to the cornea in herpes simplex virus interstitial keratitis in humans

Herpes stromal keratitis (HSK) is a prevalent and frequently vision-threate ning disease associated with herpes simplex virus type 1 (HSV-1) infection. In mice, HSK progression occurs after viral clearance and requires T cells and neutrophils. One model implicates Th1-like CD4 T cells with cross-reac tivity between the HSV-1 protein UL6 and a corneal autoantigen. HSK can be prevented by establishing specific immunological tolerance. However, HSK ca n also occur in T-cell receptor-transgenic X SCID mice lacking HSV-specific T cells. To study the pathogenesis of HSK in the natural host species, we measured local HSV-specific T-cell responses in HSK corneas removed at tran splant surgery (n = 5) or control corneas (n = 2). HSV-I DNA was detected b y PCR in two specimens. HSV-specific CD4 T cells were enriched in three of the five HSK specimens and were not detectable in the control specimens. Re activity with peptide epitopes within the tegument proteins UL21 and UL49 w as documented. Responses to HSV-I UL6 were not detected. Diverse HLA DR and DP alleles restricted these local responses. Most clones secreted gamma in terferon, but not interleukin-5, in response to antigen. HSV-specific CD8 c ells were also recovered. Some clones had cytotoxic-T-lymphocyte activity. The diverse specificities and HLA-restricting alleles of local virus-specif ic T cells in HSK are consistent with their contribution to HSK by a proinf lammatory effect.