Eosinophilic Inflammatory Disease in Mice with Limited TCR Repertoire

在淋巴细胞减少的环境如新生小鼠中或在细胞转移到遗传性淋巴细胞减少（Rag 2-/-; CD 3e-/-）受体中的淋巴细胞动力学的研究表明，在一些转移的细胞部分上发生显著的增殖反应，并且这些细胞在一周内经历7次或更多次细胞分裂，并且在这种非常显著的反应结束时显示记忆表型。在以前的工作中，已经表明，将CD 4 T细胞预先转移到淋巴细胞减少的受体中会阻止新引入的细胞进行快速增殖。还显示，最初转移的细胞阻断随后引入的细胞增殖的能力与第二次转移时存在的细胞的TCR库复杂性非常强地相关。因此，尽管接受了30，000或200万个CD 4 T细胞的Rag 2-/-小鼠在转移后6周具有相似数量的记忆表型CD 4 T细胞，但新引入的细胞在先前接受了30，000个细胞的宿主中显示出惊人的增殖，但在先前接受了200万个细胞的宿主中未能增殖。尽管在平衡状态下存在的细胞数量相似，但在200万个细胞的受体中TCR的复杂性远远大于30，000个细胞的受体。 单位科学家观察到，少量CD 4 T细胞的接受者最终发展成暴发性巨噬细胞/嗜酸性粒细胞肺炎，其特征在于存在交替活化的巨噬细胞、Ym 1晶体和嗜酸性粒细胞。这些小鼠还表现出嗜酸性胃炎和淋巴结中产生IL-4、IL-13和IL-5的细胞频率显著增加。这种综合征与在人类中观察到的T细胞向外周的胸腺供应有限的情况（如Omenn综合征、非典型完全DiGeorge综合征和严重联合免疫缺陷病中的母体植入）具有显著的关系。如果在缺乏T细胞但表达B细胞的小鼠（CD 3 e-/-小鼠）中进行转移，则观察到血清IgE的显著诱导。 调节性T细胞的预转移阻断了由有限数量的常规CD 4 T细胞的转移诱导的嗜酸性粒细胞炎性疾病的诱导，但仅当最初转移的调节性T细胞的数量相对较大（300，000）时。 预转移30，000个调节性T细胞不会阻断疾病的诱导，即使在引入常规T细胞时调节性T细胞的数量相同（由于稳态扩增）。这意味着调节性T细胞必须具有足够复杂的TCR库，以允许它们阻断常规T细胞的活化和由这些细胞介导的疾病诱导。从转移的群体中严格去除Treg细胞已被用于确定当前体数量低时Th 2分化的偏好是否仅仅是由于存在较少的T细胞。然而，利用来自Foxp 3指示小鼠的细胞，似乎清楚的是，情况并非如此，并且细胞数量是关键的确定性问题。 进一步支持的概念，有限的受体复杂性导致免疫病理学和有利于Th 2反应是来自两个额外的实验系统。 基于其仅具有单个VbDbJb链和单个Va而具有有限TCR库的小鼠也已显示发展严重的嗜酸性粒细胞炎性疾病并累及肺。 此外，可以研究来自5C.Cy7Vb链转基因小鼠的T细胞与TCR四聚体相互作用的亲合力。 因此，具有高亲合力的interqct不太可能发育成Th 2细胞，而与四聚体结合差或仅在高肽浓度下结合的interqct更可能发育成Th 2细胞。 因此，以一种以上的方式实现的有限的库对于Th 2表型的发展和推测对于自身炎性疾病具有类似的意义。

Studies of lymphocyte dynamics in lymphopenic environments such as the neonatal mouse or in cell transfer into genetically lymphopenic (Rag2-/-; CD3e-/-) recipients indicate that a striking proliferative response occurs on the part of some of the transferred cells and that such cells undergo 7 or more cell divisions within one week and display a memory phenotype at the end of this very striking response. In previous work, it was shown that the pre-transfer of CD4 T cells into lymphopenic recipients would prevent newly introduced cells from undergoing rapid proliferation. It was also shown that the capacity of the initially transferred cells to block proliferation by subsequently introduced cells correlated very strongly with the TCR repertoire complexity of the cells present as the time of the second transfer. Thus, although Rag2-/- mice that had received 30,000 or 2 million CD4 T cells had similar numbers of memory phenotype CD4 T cells 6 weeks after transfer, newly introduced cells showed striking proliferation in a host that had previously received 30,000 cells but failed to proliferate in a host that had previously received 2 million cells. The TCR complexity was far greater in the recipients of 2 million cells than in the recipients of 30,000 cells despite the similar numbers of cells present at equilibrium. Unit scientists observed that recipients of small numbers of CD4 T cells eventually developed a fulminant macrophage/ eosinophil pneumonia, characterized by the presence of alternatively activated macrophages, Ym1 crystals and eosinophils. These mice also showed an eosinophilic gastritis and a striking increase in the frequency of cells that produced IL-4, IL-13 and IL-5 in the lymph nodes. This syndrome bears a striking relationship to that observed in humans in which there is a limitation of thymic supply of T cells to the periphery, such as Omenn's syndrome, atypical complete DiGeorge syndrome and maternal engraftment in severe combined immunodeficiency disease. If the transfers are carried out in mice that lack T cells but express B cells (CD3e-/- mice), profound induction of serum IgE is observed. Pre-transfer of regulatory T cells blocks the induction of the eosinophilic inflammatory disease induced by transfer of limited numbers of conventional CD4 T cells but only when the number of initially transferred regulatory T cells is relatively large (300,000). Pre-transfer of 30,000 regulatory T cells does not block induction of disease even though the number of regulatory T cells at the time of the introduction of the conventional T cells is the same (as a result of homeostatic expansion). This implies that regulatory T cells must have a sufficiently complex TCR repertoire to allow them to block activation of conventional T cells and of disease induction mediated by these cells. Rigorous depletion of Treg cells from transferred populations has been used to determine whether the preference of Th2 differentiation when precursor number is low is simply due to the presence of fewer T regs. However, making use of cells from Foxp3 indicator mice, it seems clear that this is not the case and cell number is a critical deterministic issue. Further support for the concept that limited receptor complexity leads to immunopathology and favors a Th2 response is derived from two additional experimental systems. Mice with limited TCR repertoires based on their possessing only a single VbDbJb chain and a single Va have also been shown to develop severe eosinophilic inflammatory disease with involvement of the lung. In addition, T cells from mice transgenic for the 5C.Cy7 Vb chain can be studied for their avidity of interaction with a TCR tetramer. Thus that interqct with high avidity are unlikely to develop into Th2 cells whereas as those that bind the tetramer poorly or only at high peptide concentration are far more likely to develop into Th2 cells. Thus, limited repertoires achieved in more than one manner have similar implications for the development of Th2 phenotypes and presumably for autoinflammatory disease.