CTLA-4 down-regulates the protective anticryptococcal cell-mediated immuneresponse

Cell-mediated immune (CMI) responses defined by delayed-type hypersensitivi ty (DTH) reactivity to cryptococcal culture filtrate antigen (CneF) can be either protective or nonprotective against an infection with Cryptococcus n eoformans. The protective and nonprotective anticryptococcal DTH responses are induced by different immunogens and have differing activated-T-cell pro files. This study examined the effects of blockade of the interaction betwe en cytotoxic T lymphocyte antigen 4 (CTLA-4) and its ligands B7-1 (CD80) an d B7-2 (CD86) on the anticryptococcal DTH responses and protection. We foun d that CTLA-4 blockade at the time of immunization with the immunogen that induces the protective response, CneF, in complete Freund's adjuvant (CFA) or the immunogen that induces the nonprotective response, heat-killed crypt ococcal cells (HKC), enhanced anticryptococcal DTH reactivity. In contrast, blocking CTLA-4 after the immune response was induced failed to enhance re sponses. Blockade of CTLA-4 in an infection model resulted in earlier devel opment of the anticryptococcal CMI response than in control mice. Concomita nt with increases in DTH reactivity in mice treated with anti-CTLA-4 Fab fr agments at the time of immunization, there were decreases in cryptococcal C FU in lungs, spleens, and brains compared to controls. Blockade of CTLA-4 r esulted in long-term protection, as measured by significantly increased sur vival times, only in mice given the protective immunogen, CneF-CFk Anti-CTL A-4 treatment did not shift the response induced by the nonprotective immun ogen, HKC, to a long-term protective one. Our data indicate that blockade o f CTLA-4 interactions with its ligands may be useful in enhancing host defe nses against C. neoformans.