STUDIES WITH MHC-DEFICIENT KNOCK-OUT MICE REVEAL IMPACT OF BOTH MHC I-DEPENDENT AND MHC II-DEPENDENT T-CELL RESPONSES ON LISTERIA-MONOCYTOGENES INFECTION

Mutant mice with a defined genetic defect in the beta(2)-microgiobulin (beta(2)m) or the H2-I-A beta chain, which are virtually devoid of fu nctional CD8 or CD4 alpha beta T cells, respectively, were employed fo r analyzing immune mechanisms involved in acquired resistance against Listeria monocytogenes. Although the lethal dose of L. monocytogenes w as markedly lower for either mouse mutant as compared with their heter ozygous control littermates, both beta(2)m(-/-) and A beta(-/-) mutant s were able to resolve low dose infection. However, in both mouse muta nts, the course of disease was exacerbated and clearance was markedly delayed. Vaccine induced immunity against a secondary high dose infect ion lethal for naive animals was also impaired in beta(2)m(-/-) A beta (-/-) mice. However, both mutant mice were still capable of controllin g secondary infection. Based on numbers of L. monocytogenes organisms in spleens, beta(2)m(-/-) mutants suffered more dramatically from prim ary and secondary infection than A beta(-/-) mice. Ag-induced IFN-gamm a secretion was impaired during the early phase of infection in beta(2 )m(-/-) mice and at later stages in A beta(-/-) mice. Modulation of ga mma delta T cells by mAb treatment led to significant increase in bact erial load of spleens in both beta(2)m(-/-) and A beta(-/-) mice. Fina lly, the development of granulomatous lesions was markedly affected in both mutants. In beta(2)m(-/-) mutants, infiltrative lesions appeared and in A beta(-/-) mice few inflammatory islets with necrotic centers developed. These data demonstrate the importance of both MHC I- and M HC II-dependent immune mechanisms in acquired resistance to L. monocyt ogenes and point to the necessity of a coordinated interaction between CD8 and CD4 alpha beta T cells (and probably gamma delta T cells) in anti-L. monocytogenes resistance.