以組織胞漿菌感染小鼠探討低MHC class II表現對T細胞活化的影響

Abstract

主要組織相容性複合體第二型(MHC class II)為特化性之分子，主要功能為呈現蛋白質教育及活化CD4 T細胞。當MHC class II發生突變，會導致CD4 T細胞喪失，並使免疫系統功能下降。因此MHC class II在免疫系統對抗外來物上扮演重要的角色。然而，先前的研究只能利用MHC class II基因剔除鼠，來探討其對於CD4 T細胞的活化與對抗外來物的能力上做研究，無法更進一步了解MHC class II表現量的多少是否會影響CD4 T細胞的反應。在我的實驗中利用ENU刺激產生的基因突變鼠P235做實驗，其特徵為MHC class II表現量低。因此，我可利用P235的特性來探討MHC class II的表現量與CD4 T細胞反應的關聯性。 在我的研究中，我利用組織胞漿菌感染小鼠模式來探討感染後的T細胞反應是否會受到MHC class II表現量低而改變。我發現P235感染組織胞漿菌後的不同天數，CD4以及CD8 T細胞的數量較正常老鼠低。除此之外，產生IFN-γ與TNF-α的CD4與CD8 T細胞的數量也下降。同樣的，T細胞所產生的IFN-γ與TNF-α量也較正常老鼠低。因此，P235感染組織胞漿菌後其T細胞的活性較正常鼠弱。然而，在我的研究中發現，MHC class II表現量低並不會影響到T細胞的Vβ使用。並且與正常鼠同樣能增加整體Vβ的活化。最後，在我的研究中更進一步探討P235清除體內組織胞漿菌的能力。我的實驗發現，P235清除體內組織胞漿菌的能力並不會因T細胞活性降低而受到影響。 根據以上的實驗，我們了解了組織胞漿菌感染模式中，低MHC class II表現影響了T細胞的活性。但為何較低的T細胞活性不影響清除組織胞漿菌的能力仍然有待進一步的研究做更深入的探討。

MHC class II molecules are important in positive and negative selections of CD4 T cells in the thymus and are specialized in presenting antigenic peptides to CD4 T cells in the periphery. Engagement of MHCII-peptide complex and TCR is important to CD4 T cell activation. It has been reported that MHC class II deficiency leads to defective CD4 T cell development which in turn results in severe immunodeficiency. Studies on the role of MHC II in immune response have relied mainly on MHC II knockout mice. The question of whether low MHC II expression affects peripheral T cell responses has never been addressed. The availability of ENU-mutagenized mice P235 presents an opportunity to study how low MHC class II expression affects T cell responses to infection. In the present study, I found that T cell responses were reduced in P235 mice after infection with Histoplasma capsulatum (Hc), including both the numbers of activated CD4 and CD8 T cells and the cytokine producing ability of CD4 T cells. The TCR Vβ repertoire in naïve P235 mice was not different from that in WT mice. Upon infection by Histoplasma capsulatum, all CD4 and CD8 T cell Vβ populations expanded in P235 mice as well as in WT mice, but the expansion was limited in P235 mice. Interestingly, with lower T cell responses in P235 mice, their ability to clear the fungus at 1/100 of lethal dose was as efficient as in WT mice. Based on the results, it was clear that low MHC II expression reduces T cell responses to infection by Histoplasma capsulatum. The mechanism by which lower T cell responses not affecting fungal clearance still awaits to be investigated.