Peptide-MHCII stability impacts Th cell clonal selection

Adaptive immune responses against many pathogens and protein vaccines rest upon T helper (Th) cells recognition of specific peptide-MHC class II complexes (pMHCII). pMHCII select Th cells with T-cell receptors (TCR) of sufficient binding strength to clonally expand and differentiate into effector cells. The basic mechanisms underlying this selection processes in vivo are poorly understood. The stability of the pMHCII complexes has been shown to influence peptide immunodominance and to alter Th cell differentiation. Whether pMHCII stability impacts Th cell clonal selection is not known. We hypothesize that weakly stable pMHCII preferentially select high affinity Th cell clones, while stable pMHCII broaden the Th cell repertoire by additionally recruiting low affinity Th cell. The goal of this study is to determine the importance of pMHCII stability for Th cell clonal selection. The two specific aims are: 1) To define the impact of pMHCII stability on PCC-specific Th cell repertoire. The murine immune response to pigeon cytochrome c (PCC) is the best experimental model to study antigen- specific Th cell selection in vivo. The PCC immunodominant peptide (PCC88-103 ) misses one anchor residue, which decreases its binding to the murine MHCII molecule I-Ek . In aim 1 we will analyze how altered peptides with different stability for I-Ek alter the PCC-specific Th cell repertoire. 2) To determine the importance of pMHCII stability in shaping Influenza-specific Th cells response. The binding of Influenza hemagglutinin peptide (HA 306-318 ) to human HLA-DR1 is one of the best described models of peptide- MHCII interaction. In aim 2 we will use mice transgenic for human HLA-DR1 and examine how altered HA peptides with different binding stability for HLA-DR1 will alter the HA-specific Th cell repertoire. The outcome of this project will add valuable information to our understanding of Th cell selection during adaptive immune responses. Such knowledge is of fundamental interest with potentially high impact on the public health initiative of vaccine design.