Functional hierarchy and relative contribution of the CD28/B7 and ICOS/B7-H2 costimulatory pathways to T cell-mediated delayed-type hypersensitivity.

The CD28/B7 and ICOS/B7-H2 pathways are both critical for costimulating T cell immune responses. Deficiency in either pathway results in defective T cell activation, cytokine production and germinal center formation. However, the relative importance and contribution of each pathway towards T cell-mediated immunity is still not clear. To address this issue, we compared T cell responses of WT, CD28 knockout (KO), B7-H2 KO, and CD28-B7-H2 double KO (DKO) mice in a model of delayed-type hypersensitivity (DTH). While CD28 KO mice have partially compromised DTH response, DKO mice exhibited greatly diminished response, suggesting that the ICOS/B7-H2 pathway could partially compensate for the costimulation of DTH. Surprisingly, B7-H2 KO mice had comparable DTH response as WT mice, indicating that the ICOS/B7-H2 pathway is secondary to the CD28/B7 pathway in costimulating DTH. Interestingly, prolonging the period of sensitization could overcome the compromised DTH response in CD28 KO but not DKO mice, revealing a novel form of functional redundancy of ICOS/B7-H2 costimulation that is dependent on time to take effect. Taken together, our data reveal a functional hierarchy of the CD28/B7 and ICOS/B7-H2 pathways and delineated their relative contributions to the elicitation of a DTH response.