Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 131, Issue 2, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI136574
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Funding
- National Institutes of Health [T32GM007863, F30AI145113, R01HL148333, R35HL135793]
- National Institutes of Health (NHLBI) [R01HL128046]
- National Institutes of Health (NCI) [R01CA203542, R01CA217156]
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The activation of T cells leads to increased trafficking via the ER-to-Golgi pathway, which is crucial for the regulation of T cell secretome. Deficiency of SEC23B may impair T cell functions, while increased levels of SEC23A in CDAII patients' T cells contribute to maintaining their functions.
T cell-mediated responses are dependent on their secretion of key effector molecules. However, the critical molecular determinants of the secretion of these proteins are largely undefined. Here, we demonstrate that T cell activation increases trafficking via the ER-to-Golgi pathway. To study the functional role of this pathway, we generated mice with a T cell-specific deletion in SEC23B, a core subunit of coat protein complex II (COPII). We found that SEC23B critically regulated the T cell secretome following activation. SEC23B-deficient T cells exhibited a proliferative defect and reduced effector functions in vitro, as well as in experimental models of allogeneic and xenogeneic hematopoietic cell transplantation in vivo. However, T cells derived from 3 patients with congenital dyserythropoietic anemia II (CDAII), which results from Sec23b mutation, did not exhibit a similar phenotype. Mechanistic studies demonstrated that unlike murine KO T cells, T cells from patients with CDAII harbor increased levels of the closely related paralog, SEC23A. In vivo rescue of murine KO by expression of Sec23a from the Sec23b genomic locus restored T cell functions. Together, our data demonstrate a critical role for the COPII pathway, with evidence for functional overlap in vivo between SEC23 paralogs in the regulation of T cell immunity in both mice and humans.
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