Peptide analogs with different affinites for MHC alter the cytokine profile of T helper cells.

The interaction of the TCR with the immunogenic peptide bound to MHC class II molecules leads to the activation of the CD4(+) T helper cells. T helper cells have been divided into two subsets, Th1 and Th2, on the basis of the cytokines secreted by them. Th1 cells which secrete IL-2, IFN-gamma and tumor necrosis factor-beta induce delayed-type hypersensitivity, while Th2 cells secreting IL-4, IL-5, IL-6 and IL-10 induce humoral immune response. However, the mechanism of selective activation of Th1 and Th2 cells in response to different antigens is not fully understood. In this study we examined the selective activation of Th1 and Th2 cells in response to strongly immunogenic synthetic peptides EYK(EYA)3, abbreviated as K3; EYK(EYA)4, abbreviated as K4; and EYKEYAAYA(EYA)2, abbreviated as K1A2. These peptides are recognized by H-2(d) T cells in the context of I-Ad, and are strongly cross-reactive in both T cell response and antibody response. The peptide K1A2 has very high affinity for I-Ad while K3 has a much lower affinity. K4 has affinity intermediate between K1A2 and K3. The peptide K1A2 induced Th1 and K3 induced Th2 cells in BALB/c mice as suggested by their cytokine profiles. K4 induced both Th1- and Th2-type cytokines. This was also confirmed by the analysis of both IgG1 and IgG2a responses in vivo. There was a shift toward a Th1-type cytokine profile when K3-primed T cells were challenged with K1A2 in vitro but K1A2-primed cells did not show any shift when challenged with K3. Immunization with higher doses of K3 shifted the response towards Th1 type, while immunization with lower doses of K1A2 did not shift the response toward Th2. We conclude that cells primed with high-affinity peptide are committed to differentiate into Th1 irrespective of the priming dose and affinity of challenge antigen. On the other hand, the differentiation of cells primed with low-affinity peptide depends upon the dose of immunization and binding affinity of the challenge antigen for MHC.