Th cells are the master regulators of adaptive immunity and have critical impact on the quality of antigen-specific B cell responses to protein antigen immunization. We have recently focused on a phenotypic divide that exists in the pre-immune Th cell compartment that turns out to have substantial impact on antigen-driven Th cell function in vivo. The Th cell phenotypic divide based on Ly6C expression, has its origins in thymic maturation and correlates with the uneven assortment of the pre-immune TCR repertoire for Th cells. Naive Th cells with different TCR profiles, but specificity for the same foreign peptide epitope, assort Ly6Chi and Ly6CIo prior to immunization with the antigen. In this manner, two separate sets of naive Th cells can be recruited into the response to the same foreign antigen. We seek to understand the impact of this peripheral cell fate division on the development of antigen-specific B cell immunity in vivo. Understanding the role of pre-immune functional diversity on the development of Th cell-regulated B cell immunity is of fundamental interest with potentially high impact on the public health initiative of vaccine design. In our initial studies, we demonstrate a substantial difference in the capacity of each Th cell subset to promote plasma cell development in the primary B cell response. These data suggest that the different Th cell subsets develop distinct Th effector functions and may also establish unique memory Th cell compartments. We will determine the impact of Ly6Chi and Ly6CIo Th cells on B cell immunity (SAI). It will be important to examine how these Th cell subsets and their progeny regulate adaptive immunity (SAll). Finally, we will evaluate how innate immunity controls the two Th cell subsets and development of effector function (SAIII).