The diverse response of individuals within populations to infectious pathog
ens remains poorly understood, although genetic determinants undoubtedly co
ntribute in substantial ways to the outcome of infection. In a mouse model
of infection with the intramacrophage protozoan Leishmania major, susceptib
ility correlates both with aberrant helper T cell differentiation biased to
wards the production of interleukin 4 and with the presence of an endogenou
s CD4 T cell repertoire that recognizes an immunodominant parasite antigen
with high frequency. In the setting of the particular ecological niche occu
pied by Leishmania, this combination of otherwise unrelated factors synergi
zes to result in exquisite susceptibility to this single pathogen, without
seemingly compromising host defenses against other agents. Similar paradigm
s could underlie susceptibility to other pathogenic organisms.