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

Summary

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-2^b) mice and H-2Kb mutant B6.C-H-2^bm1 (bm1) mice. These two mouse strains differ from each other only in three amino acids in the crucial H-2K^b 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-2^b 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-2K^b restricted B6 Tc clone. In vivo protection by this Tc clone is H-2K^b 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-A^b 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.