Memory CD4 T cell driven antibody responses to renal allografts

尽管改善免疫抑制和常规PRA筛查，同种异体反应性抗体（alloAb）介导的急性同种异体移植排斥反应事件的显着比例，并有助于慢性排斥反应的发展。致病性同种抗体同种型的产生需要B细胞和对供体抗原特异性的辅助CD 4 T细胞之间的相互作用。通常，这种帮助发生在次级淋巴器官内的生发中心，并依赖于CD 40/CD 154共刺激通路。然而，许多人的T细胞库包含对免疫抑制或共刺激阻断具有抗性的同种异体反应性记忆T细胞。我们的初步数据显示，即使在没有常规生发中心形成和CD 40/CD 154相互作用的情况下，与初始CD 4 T细胞相比，供体反应性记忆CD 4 T细胞诱导更高滴度的alloAb。然而，所观察到的高alloAb滴度的机制以及记忆性CD 4 T细胞帮助的解剖部位和分子要求仍然未知，需要进行测试。本研究的目的是确定记忆性CD 4 T细胞的功能表型，为同种异体反应性B细胞提供帮助，并调查这种帮助的特征和要求。我们建立了小鼠肾移植模型，研究记忆性CD 4 T细胞诱导的供体特异性alloAb应答。我们假设，与幼稚细胞相比，记忆性CD 4 T细胞启动GC的增强发育和B细胞的更大增殖，促进对供体抗原具有更高亲和力的alloAb的产生，并诱导长寿命Ab分泌浆细胞和记忆性B细胞的增强发育。我们进一步提出，虽然与其他谱系相比，滤泡辅助记忆T细胞在诱导alloAb应答方面具有上级优势，但记忆CD 4 T细胞的帮助可以发生在典型的生发中心之外，并且可以通过替代分子途径（如TLR和BAFF/APRIL信号传导）绕过对CD 40/CD 154相互作用的要求。我们将在三个具体目标中检验这一假设：目标1。目的：探讨供者特异性记忆性CD 4 T细胞诱导上级异体抗体产生的机制。目标2.目的：鉴定记忆性CD 4 T细胞的功能表型，为同种异体肾移植后产生同种抗体提供帮助。目标3.确定记忆性CD 4 T细胞产生同种抗体的位置和分子要求。

Despite improved immunosuppression and routine PRA screening, alloreactive antibodies (alloAb) mediate a significant proportion of acute allograft rejection episodes and contribute to the development of chronic rejection. Production of pathogenic alloAb isotypes requires interactions between B cells and helper CD4 T cells specific for donor antigens. Typically, this help occurs in germinal centers within secondary lymphoid organs and is dependent on CD40/CD154 costimulatory pathway. However, the T cell repertoire of many humans contains alloreactive memory T cells that are resistant to immunosuppression or costimulatory blockade. Our preliminary data show that donor-reactive memory CD4 T cells induce higher titers of alloAb compared to naive CD4 T cells even in the absence of conventional germinal center formation and CD40/CD154 interaction. However, the mechanisms underlying the observed high alloAb titers as well as anatomical sites and molecular requirements of help by memory CD4 T cells are still unknown and need to be tested. The goal of this study is to identify functional phenotype of memory CD4 T cells providing help for alloreactive B cells and to investigate the characteristic features and requirements for this help. We have developed a mouse model of kidney transplantation to study donor-specific alloAb responses induced by memory CD4 T cells. We hypothesize that compared to naive cells, memory CD4 T cells initiate enhanced development of GCs and greater proliferation of B cells, promote production of alloAb with higher affinities for donor antigens and induce enhanced development of long-lived Ab secreting plasma cells and memory B cells. We further propose that while follicular helper memory T cells are superior in inducing alloAb responses compared to other lineages, help by memory CD4 T cells can occur outside of typical germinal centers and can bypass the requirement for CD40/CD154 interaction via alternative molecular pathways such as TLR and BAFF/APRIL signaling. We will test this hypothesis in three Specific Aims: Aim 1. To investigate the mechanisms of superior alloantibody production induced by donor-specific memory CD4 T cells in response to renal allografts. Aim 2. To identify functional phenotype of memory CD4 T cells capable of providing help for alloantibody production after renal allograft placement. Aim 3. To determine the location and molecular requirements of help provided by memory CD4 T cells for alloantibody production.