Key Points
Arf1 and Arf6 are dispensable for cytokine secretion in T cells.
Arf1 and Arf6 redundantly protect activated naive T cells from apoptosis.
Loss of Arf1 and Arf6 in T cells alleviates autoimmune diseases.
Abstract
ADP-ribosylation factor (Arf) family consisting of six family members, Arf1–Arf6, belongs to Ras superfamily and orchestrates vesicle trafficking under the control of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins. It is well established that brefeldin A, a potent inhibitor of ArfGEFs, blocks cytokine secretion from activated T cells, suggesting that the Arf pathway plays important roles in T cell functions. In this study, because Arf1 and Arf6 are the best-characterized members among Arf family, we established T lineage–specific Arf1-deficient, Arf6-deficient, and Arf1/6 double-deficient mice to understand physiological roles of the Arf pathway in the immune system. Contrary to our expectation, Arf deficiency had little or no impact on cytokine secretion from the activated T cells. In contrast, the lack of both Arf1 and Arf6, but neither Arf1 nor Arf6 deficiency alone, rendered naive T cells susceptible to apoptosis upon TCR stimulation because of imbalanced expression of Bcl-2 family members. We further demonstrate that Arf1/6 deficiency in T cells alleviates autoimmune diseases like colitis and experimental autoimmune encephalomyelitis, whereas Ab response under Th2-polarizing conditions is seemingly normal. Our findings reveal an unexpected role for the Arf pathway in the survival of T cells during TCR-induced activation and its potential as a therapeutic target in the autoimmune diseases.
Footnotes
This work was supported in part by Japan Society for the Promotion of Science grants-in-aid for scientific research (19K16701 to M.S. and 20K07555 and 20H03776 to S.M.), a Kansai Medical University grant-in-aid for research (to M.S.), the branding program as a world-leading research university on intractable immune and allergic diseases supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Kansai Medical University Molecular Imaging Center of Diseases.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- 7-AAD
- 7-aminoactinomycin D
- Arf
- ADP-ribosylation factor
- Arf1-KO
- T lineage–specific Arf1-deficient
- Arf1/6-KO
- T lineage–specific Arf1/Arf6 doubly deficient
- Arf6-KO
- T lineage–specific Arf6-deficient
- γc
- common γ-chain
- DP
- double-positive
- EAE
- experimental autoimmune encephalomyelitis
- eF450
- Cell Proliferation Dye eFluor 450
- GAP
- GTPase-activating protein
- GC
- germinal center
- GEF
- guanine nucleotide exchange factor
- IBD
- inflammatory bowel disease
- LP
- lamina propria
- MLN
- mesenteric lymph node
- MOG
- myelin oligodendrocyte glycoprotein
- MS
- multiple sclerosis
- NAC
- N-acetyl-l-cysteine
- PP
- Peyer patch
- ROS
- reactive oxygen species
- SAS
- Sigma Adjuvant System
- SP
- single-positive
- Treg
- regulatory T cell.
- Received August 24, 2020.
- Accepted November 12, 2020.
- Copyright © 2021 by The American Association of Immunologists, Inc.
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