Karamooz Elham, Kim Se-Jin, Peterson Jessie C, Tammen Allison E, Soma Shogo, Soll Aviva C R, Meermeier Erin W, Khuzwayo Sharon, Lewinsohn David M
Portland VA Medical Center, Portland, Oregon United States of America.
Pulmonary & Critical Care Medicine, Oregon Health & Science UniversityPortland, Oregon, United States of America.
PLoS Pathog. 2025 Aug 4;21(8):e1013342. doi: 10.1371/journal.ppat.1013342. eCollection 2025 Aug.
MR1 is a ubiquitously expressed MHC-Ib molecule that presents microbial metabolites to MR1-restricted T cells, but there are differences in the antigen presentation pathway of an intracellular microbe compared to exogenously delivered antigen. We have shown the importance of endosomal trafficking proteins in MR1-dependent presentation of Mycobacterium tuberculosis (Mtb) infection. Two pore channels (TPCs) are endosomal calcium channels that regulate endosomal trafficking. Due to their location on endosomes, we hypothesized that TPCs could be required for MR1-dependent presentation of antigens derived from the intracellular microbe Mtb. We found that TPC1 is critical for the presentation of Mtb infection by MR1; inhibition of TPCs had no effect on MR1 presentation of exogenously delivered antigens, HLA-B presentation, or HLA-II presentation. Finally, we found that the calcium-sensitive trafficking protein Synaptotagmin 7 was also key in the presentation of Mtb infection by MR1. TPC1 and Synaptotagmin 7 may be part of an endosomal pathway by which MR1 can sample intracellular mycobacterial infections.
MR1是一种广泛表达的MHC-Ib分子，它将微生物代谢产物呈递给受MR1限制的T细胞，但与外源性递送的抗原相比，细胞内微生物的抗原呈递途径存在差异。我们已经证明了内体运输蛋白在结核分枝杆菌（Mtb）感染的MR1依赖性呈递中的重要性。双孔通道（TPCs）是调节内体运输的内体钙通道。由于它们在内体上的位置，我们推测TPCs可能是MR1依赖性呈递源自细胞内微生物Mtb的抗原所必需的。我们发现TPC1对MR1呈递Mtb感染至关重要；抑制TPCs对外源性递送抗原的MR1呈递、HLA-B呈递或HLA-II呈递没有影响。最后，我们发现钙敏感运输蛋白突触结合蛋白7在MR1呈递Mtb感染中也起关键作用。TPC1和突触结合蛋白7可能是MR1能够对细胞内分枝杆菌感染进行取样的内体途径的一部分。
