Functional Diversity in Pre-Immune Helper T Cells

描述(由申请人提供)：TH细胞是适应性免疫的主要调节者，对蛋白质抗原免疫的抗原特异性B细胞反应的质量具有关键影响。我们最近专注于存在于免疫前Th细胞隔间的表型分裂，事实证明，这种分裂对体内抗原驱动的Th细胞功能有实质性影响。基于Ly6C表达的Th细胞表型分裂起源于胸腺成熟，并与Th细胞免疫前TCR谱系的不均匀分类有关。具有不同TCR谱但对同一外源多肽表位具有特异性的幼稚Th细胞，在用该抗原免疫之前将Ly6chi和Ly6CIo进行配对。通过这种方式，两组不同的原始Th细胞可以被招募到对同一外来抗原的反应中。我们试图了解这种外周细胞命运分裂对体内抗原特异性B细胞免疫发展的影响。 了解免疫前功能多样性在Th细胞调节的B细胞免疫发展中的作用具有基本的兴趣，对疫苗设计的公共卫生倡议具有潜在的高度影响。在我们最初的研究中，我们证明了在初级B细胞反应中，每个Th细胞亚群促进浆细胞发育的能力有很大的差异。这些数据表明，不同的Th细胞亚群发展了不同的Th效应功能，也可能建立了独特的记忆Th细胞室。我们将确定Ly6chi和Ly6CIo Th细胞对B细胞免疫(SAI)的影响。研究这些Th细胞亚群及其后代如何调节获得性免疫(SAL)将是很重要的。最后，我们将评估先天免疫如何控制这两个Th细胞亚群和效应功能的发展(SAIII)。

DESCRIPTION (provided by applicant): 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).