Changhong Wu

T lymphocytes are pivotal in adaptive immunity. The role of the trafficking protein particle complex (TRAPPC) in regulating T‐cell development and homeostasis is unknown. Using CD4^cre‐Trappc1^flox/flox (Trappc1 cKO) mice, we found that Trappc1 deficiency in T cells significantly decreased cell number of naive T cells in the periphery, whereas thymic T‐cell development in Trappc1 cKO mice was identical as WT mice. In the culture assays and mouse models with adoptive transfer of the sorted WT (CD45.1⁺CD45.2⁺) and Trappc1 cKO naive T cells (CD45.2⁺) to CD45.1⁺ syngeneic mice, Trappc1‐deficient naive T cells showed significantly reduced survival ability compared with WT cells. RNA‐seq and molecular studies showed that Trappc1 deficiency in naive T cells reduced protein transport from the endoplasmic reticulum to the Golgi apparatus, enhanced unfolded protein responses, increased P53 transcription, intracellular Ca²⁺, Atf4‐CHOP, oxidative phosphorylation, and lipid peroxide accumulation, and subsequently led to ferroptosis. Trappc1 deficiency in naive T cells increased ferroptosis‐related damage‐associated molecular pattern molecules like high mobility group box 1 or lipid oxidation products like prostaglandin E2, leukotriene B4, leukotriene C4, and leukotriene D4. Functionally, the culture supernatant of Trappc1 cKO naive T cells significantly promoted neutrophils to express inflammatory cytokines like TNFα and IL‐6, which was rescued by lipid peroxidation inhibitor Acetylcysteine. Importantly, Trappc1 cKO mice spontaneously developed severe autoinflammatory disease 4 weeks after birth. Thus, intrinsic expression of Trappc1 in naive T cells plays an integral role in maintaining T‐cell homeostasis to avoid proinflammatory naive T‐cell death‐caused autoinflammatory syndrome in mice. This study highlights the importance of the TRAPPC in T‐cell biology.

Whether induced tissue-resident memory T (T _RM ) cells in nonlymphoid organs alone can mediate allograft rejection is unknown. By grafting alloskin or heart into severe combined immunodeficient or Rag2KO mice in which a piece of induced CD4 ⁺ and/or CD8 ⁺ T _RM cell–containing MHC-matched or syngeneic skin was transplanted in advance, we addressed this issue. The induced CD4 ⁺ T _RM cells in the skin alone acutely rejected alloskin or heart grafts. RNA-seq analysis showed that induced CD4 ⁺ T _RM cells in skin favorably differentiated into T _H 17-like polarization during the secondary immune response. Inhibition of the key T _H 17 signaling molecule RORγt attenuated T _RM cell–mediated graft rejection. Thus, we offer a unique mouse model to specifically study T _RM cell–mediated allograft rejection without the involvement of lymphocytes in lymphoid organs and tissues. Our study provides strong evidence supporting the hypothesis that long-lived alloreactive T _RM cells resident in other organs/tissues substantially contribute to organ allograft rejection.