Heterologous immunity associated with cross-reactive T-cell responses is proposed to contribute to variations among individuals in the pathogenesisA number of studies have shown that T cell responses to viral infections may be influenced by memory T cells generated in response to unrelated pathogens. [1][2][3][4][5] This alteration in responses is displayed by changes in T cell immunodominance hierarchies, 1 by alterations in viral loads and protective immunity, and by marked changes in immunopathology. 2,4 This "heterologous immunity" can be a consequence of unanticipated T cell cross-reactivity between different pathogens. Indeed, T cell specificity can be quite degenerate, and cross-reactivity between different viruses is common. For example, human studies have revealed strong T cell cross-reactivity between influenza A virus (IAV) and Epstein-Barr virus (EBV) epitopes and between IAV and hepatitis C virus (HCV) epitopes. Acute infectious mononucleosis and fulminant hepatitis have been suggested as pathological manifestations of such CD8 T cell cross-reactivity. 3,5 Heterologous immunity can best be studied and manipulated in mouse model systems, and C57BL/6 mice immune to lymphocytic choriomeningitis virus (LCMV) and subsequently challenged with vaccinia virus (VV) show enhanced protective immunity and altered immunopathology, in contrast to naïve mice infected with VV.2,4 These are manifestations of heterologous immunity that can be duplicated by transfer of LCMV-immune T cell populations into naïve mice, followed by challenge with VV. VV challenge of LCMV-immune mice by the i.p. route results in a severe panniculitis, or inflammation of visceral fat, with pathology similar to that of human erythema nodosum. The fat tissue is infiltrated with T cells crossreactive between LCMV and VV, and the pathology is dependent on interferon-␥ (IFN-␥). VV challenge of LCMVimmune mice by the intranasal route results in abnormally pronounced T cell infiltrates in the lungs, sometimes with the accompanying pathology known as bronchiolitis obliterans.A property of heterologous immunity noted both in the human and murine systems is that there can be dramatic variation in pathogenesis and in the cross-reactive specSupported by NIH grant AI-46578 (L.K.S.), AI-46629 (L.K.S.), and AR35506 (R.M.W.) and DR-32520.