Genetic Control of T-Cell and NK-Cell Protection Against Lethal Sendai Virus Infection

Abstract

The in vivo importance of class I MHC regulation of the cytotoxic T cell (Tc) response to a natural pathogenic agent of high virulence was studied on the basis of our demonstration of a major difference in the capacity to generate a Sendai virus-specific Tc response between C57BL/6 (B6, H-2b) mice and H-2Kb mutant B6.C-H-2bm1 (bm1) mice. These two mouse strains differ from each other only in three amino acids in the crucial H-2Kb restriction element for this response. Bm1 mice, in contrast to B6 mice, are Tc nonresponders against this virus, but show Sendai-specific T cell proliferation, antibody production, and delayed type hypersensitivity (DTH) reactions, as well as natural killer (NK) cell activity, equal to those of B6 mice. Another H-2b mouse strain, the 129/J, also shows equal Sendai virus-specific Tc, T helper cell (Th), B cell and DTH responses compared to B6, but is virtually deficient in generating an NK cell response. B6, Sendai Tc-deficient bm1, T cell-deficient B6 nu/nu and NK low-responder 129/J mice differ from each other in susceptibility to lethal pneumonia induced by intranasal (i.n.) inoculation of virulent Sendai virus. The lethal dose (LD50) in B6 mice averages 152 TCID50, in bm1 mice 14 TCID50, in B6 nu/nu mice 0.5 TCID50 and in 129/J mice 0.2 TCID50. The importance of Tc is shown by the difference in susceptibility between B6 and bm1 mice and also by the complete protection of B6 nu/nu mice against infection with a lethal virus dose by i.v. injection of a Sendai virus-specific, IL-2 dependent and H-2Kb restricted B6 Tc clone. In vivo protection by this Tc clone is H-2Kb restricted. Apart from Tc, an important role for virus-specific Th cells is evident from the difference in susceptibility between bm1 and B6 nu/nu mice. This conclusion is supported by the demonstration that the mean survival time of B6 nu/nu and bm1 nu/nu mice can be significantly prolonged, in an I-Ab restricted manner, by the injection of in vitro-propagated, Sendai-specific B6 or bm1 Th clones after a lethal dose of Sendai virus, and by the demonstration that inoculation of these Th clones provides help to virus-specific Tc by means of IL-2 production. Strikingly, Th and Tc cooperate in anti-Sendai virus immunity, since permanent survival of lethally infected nu/nu mice is only achieved by inoculation of a mixture of Tc and Th clones or a mixture of a Tc clone and rIL-2. Furthermore, the difference in susceptibility to Sendai virus infection between B6 and bm1 mice provides a unique model for the study of MHC-disease associations. The importance of NK cells is revealed by the high susceptibility of 129/J mice to Sendai virus infection, although all other immune parameters measured appear to be normal.