Cooperation between cytotoxic and helper T lymphocytes in protection against lethal Sendai virus infection. Protection by T cells is MHC-restricted and MHC-regulated; a model for MHC-disease associations

Abstract

The in vivo importance of class I MHC regulation of the Tc response to a natural pathogenic agent of high virulence was studied on the basis of our previous 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 (bm 1) mice. These two mouse strains differ from each other only in three amino acids in the crucial H-2Kb restriction element for this response. bm 1 mice, in contrast to B6 mice, are Tc nonresponders against this virus, but show Sendai-specific T cell proliferation, antibody production, and DTH reactions, as well as NK cell activity, equal to those of B6 mice. B6, Sendai Tc-deficient bm 1 and T cell-deficient B6 nu/nu mice differ from each other in susceptibility to lethal pneumonia induced by i.n. inoculation of virulent Sendai virus. The lethal dose (LD50) in B6 mice averaged 152 TCID50, in bm 1 mice, 14 TCID50 and in B6 nu/nu mice 0.5 TCID50. The importance of Tc was also shown 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 was H-2Kb-restricted. Apart from Tc, an important role for virus-specific Th cells is evident from the difference in susceptibility between bm 1 and B6 nu/nu mice. This conclusion was supported by the demonstration that the mean survival time of B6 nu/nu and bm 1 nu/nu mice could be significantly prolonged, in an I-Ab-restricted manner, by the injection of in vitro-propagated, Sendai-specific B6 or bm 1 Th clones after a lethal dose of Sendai virus, and by the demonstration that inoculation of these Th clones provided 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 was only achieved by inoculation of a mixture of Tc and Th clones or a mixture of a Tc clone and rIL-2. This study provides a unique model for the study of MHC-disease associations.