Cutting edge: alloimmune responses against major and minor histocompatibility antigens: distinct division kinetics and requirement for CD28 costimulation.

Comparative study of alloimmune responses against major and minor histocompatibility Ags has been limited by the lack of suitable assays. Here, we use a bioassay that permits tracking of alloreactive CD4+ T cell populations as they proliferate in response to major or minor histocompatibility Ags in vivo. Division of alloreactive CD4+ T cells proceeded more rapidly in response to major histocompatibility Ags than minor Ags, although CD4+ T cells alloreactive to minor Ags had a similar capacity to divide successively up to eight times after stimulation. Allorecognition of minor histocompatibility Ags was highly dependent on CD28 costimulation, with the frequency of CD4+ T cells proliferating in response to minor Ags in the absence of CD28 costimulation reduced up to 20-fold. These findings highlight differences in signaling processes that lead to allorecognition of major and minor histocompatibility Ags and have implications on the design of interventions aimed at abrogating these responses.