CD28 costimulation and parasite dose combine to influence the susceptibility of BALB/c mice to infection with Leishmania major

Infection with Leishmania major in BALB/c mice is accompanied by the development of a nonprotective Th2-type response. It has previously been shown that disease progression, and the activation of a Th2-type response, can occur in the absence of CD28 costimulation following the inoculation of high numbers of L major promastigotes. In this study, we show that in the absence of CD28-B7 interactions, BALB/c mice can spontaneously resolve their infections following the inoculation of low numbers of parasites. BALB/c CD28(+/+) and CD28(-/-) mice were inoculated with 250, 500, and 750 metacyclic parasites. The CD28(-/-) mice controlled their lesions, whereas the wild-type (WT) mice developed progressive nonhealing infections. Resistance to infection was associated with reduced numbers of parasites in the CD28(-/-) mice compared with the WT mice. Infection of the CD28(-/-) mice resulted in the activation of a Th1-type response as evidenced by increased levels of mRNA for IFN-gamma and reduced levels of message for IL-4 and IL-10 in draining lymph nodes compared with those in WT mice. Healing of infected CD28(-/-) mice could also be ablated with anti-CD4 Ab treatment or treatment with anti-IFN-gamma Ab. In addition, healed CD28(-/-) mice were resistant to a challenge infection with L major. These results suggest that CD28 costimulation influences the in vivo activation of a Th2-type response in a manner that is dependent on the size of the parasite inoculum.