Gut-homing Δ42PD1+Vδ2 T cells promote innate mucosal damage via TLR4 during acute HIV type 1 infection

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Abstract

The innate immune cells underlying mucosal inflammatory responses and damage during acute HIV-1 infection remain incompletely understood. Here, we report a Vδ2 subset of gut-homing γδ T cells with significantly upregulated Δ42PD1 (a PD1 isoform) in acute (~20%) HIV-1 patients compared to chronic HIV-1 patients (~11%) and healthy controls (~2%). The frequency of Δ42PD1+Vδ2 cells correlates positively with plasma levels of pro-inflammatory cytokines and fatty-acid-binding protein before detectable lipopolysaccharide in acute patients. The expression of Δ42PD1 can be induced by in vitro HIV-1 infection and is accompanied by high co-expression of gut-homing receptors CCR9/CD103. To investigate the role of Δ42PD1+Vδ2 cells in vivo, they were adoptively transferred into autologous humanized mice, resulting in small intestinal inflammatory damage, probably due to the interaction of Δ42PD1 with its cognate receptor Toll-like receptor 4 (TLR4). In addition, blockade of Δ42PD1 or TLR4 successfully reduced the cytokine effect induced by Δ42PD1+Vδ2 cells in vitro, as well as the mucosal pathological effect in humanized mice. Our findings have therefore uncovered a Δ42PD1–TLR4 pathway exhibited by virus-induced gut-homing Vδ2 cells that may contribute to innate immune activation and intestinal pathogenesis during acute HIV-1 infection. Δ42PD1+Vδ2 cells may serve as a target for the investigation of diseases with mucosal inflammation.

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Fig. 1: Δ42PD1+Vδ2 cells are found in early HIV-1 infection and correlate with immune activation.
Fig. 2: HIV-1 infection induces Δ42PD1 expression on Vδ2 cells.
Fig. 3: Preferential migration of HIV-induced CD3+Vδ2+ cells to the intestines in humanized mice.
Fig. 4: Δ42PD1 functions via TLR4 for the induction of cytokine production.
Fig. 5: Direct interaction between Δ42PD1 and TLR4.
Fig. 6: HIV-induced Δ42PD1-expressing γδ T cells can induce robust cytokines from autologous DCs via Δ42PD1–TLR4.

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Acknowledgements

The authors thank K. Miyake for providing the MD2 plasmid, K.H. Kok for CFP, YFP and NF-κB-luciferase plasmids and C. Cheng-Mayer for critical discussions. The authors thank L. Liu for technical advice with immunohistochemical staining. The authors acknowledge the Faculty Core Facility of the LKS Faculty of Medicine, HKU, for technical assistance with confocal microscopy. This work was supported by research grants from the Hong Kong Research Grant Council (RGC: HKU5/CRF/13G, RGC17103514, RGC17122915 and A-HKU709/14 to Z.C.); the Health and Medical Research Fund (HMRF: 14130582 to Z.C., 15140372 to A.K.L.C.); the San-Ming Project of Medicine in Shenzhen (to Z.C. and H.Wa.); the National Science and Technology Major Project (2012ZX10001-009-001-001 to Z.C., 2012ZX1000-1006-001-009 to H.S.) Beijing Key Laboratory of HIV/AIDS Research (BZ0089 to H.Wu) and Beijing Municipal of Science and Technology Major Project (D161100000416003 to H.Wu) and the University Development Fund of the University of Hong Kong and Li Ka Shing Faculty of Medicine Matching Fund to AIDS Institute.

Author information

A.K.L.C. and Z.C. designed experiments, analysed data and wrote the manuscript. A.K.L.C., Y.H., H.-y.K., M.C., Y.M., X.W., K.-s.L., H.-k.K, T.C.K.L., J.Z. and B.K.L. performed experiments. J.L. and L.C. generated the Δ42PD1-specific antibodies. Q.P., X.L., M.A., H.Wa., H.S., B.Z. and H.Wu provided HIV patient samples. A.X. and K.-Y.Y. provided critical comments and materials.

Correspondence to Zhiwei Chen.

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