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Frequency of Effector Memory Cells Expressing Integrin α₄β₇ Is Associated With TGF-β1 Levels in Therapy Naive HIV Infected Women With Low CD4⁺ T Cell Count.

ABSTRACT: Integrin α₄β₇ expressing CD4⁺ T cells are preferred targets for HIV infection and are thought to be predictors of disease progression. Concurrent analysis of integrin α₄β₇ expressing innate and adaptive immune cells was carried out in antiretroviral (ART) therapy naïve HIV infected women in order to determine its contribution to HIV induced immune dysfunction. Our results demonstrate a HIV infection associated decrease in the frequency of integrin α₄β₇ expressing endocervical T cells along with an increase in the frequency of integrin α₄β₇ expressing peripheral monocytes and central memory CD4⁺ T cells, which are considered to be viral reservoirs. We report for the first time an increase in levels of soluble MAdCAM-1 (sMAdCAM-1) in HIV infected individuals as well as an increased frequency and count of integrin β7Hi CD8⁺ memory T cells. Correlation analysis indicates that the frequency of effector memory CD8⁺ T cells expressing integrin α₄β₇ is associated with levels of both sMAdCAM-1 and TGF-β1. The results of this study also suggest HIV induced alterations in T cell homeostasis to be on account of disparate actions of sMAdCAM-1 and TGF-β1 on integrin α₄β₇ expressing T cells. The immune correlates identified in this study warrant further investigation to determine their utility in monitoring disease progression.

SUBMITTER: Kasarpalkar NJ

PROVIDER: S-EPMC8019712 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMesenchymal stem cells (MSCs) have been recognized as a promising tool for the treatment of various inflammatory disorders and autoimmune diseases. Stress conditions affect immune-mediated treatment and activate autophagy in MSCs. However, whether autophagy affects the MSC-mediated recruitment and differentiation of CD4+ T cells remains elusive.MethodsMSCs were pretreated with 3-methyladenine (3-MA) and rapamycin to regulate autophagy, and then co-cultured with CD4+ T cells. CD4+ T cell migration and differentiation were detected by flow cytometry. Further, gene expression levels of well-known chemokines were analyzed by quantitative real-time PCR. Enzyme-linked immunosorbent assays and western blot analysis were performed to detect C-X-C motif chemokine ligand 8 (CXCL8) and transforming growth factor (TGF)-β1 protein levels. An exogenous antibody and short hairpin RNA were used to regulate CXCL8 and TGF-β1 levels, which enabled us to evaluate how autophagy affected MSC-mediated CD4+ T cell migration and differentiation.Results3-MA inhibited autophagy in MSCs, which was activated by rapamycin. Rapamycin increased the migration of CD4+ T cells, whereas 3-MA decreased their migration. Mechanistically, we found that autophagy strengthened CXCL8 secretion, and the addition of exogenous CXCL8 and an anti-CXCL8 antibody eliminated the difference of CD4+ T cell migration among groups. Further, the ratio of regulatory T (Treg) cells was increased in rapamycin-pretreated MSCs, but the ratio of T helper 1 (Th1) cells was decreased, while pretreatment of MSCs with 3-MA induced the opposite effect compared with the control group. TGF-β1 overexpression and knockdown using lentiviruses rectified the differences in the ratios of Treg and Th1 cells among the groups.ConclusionThis study demonstrates that autophagy of mesenchymal stem cells mediates CD4+ T cell migration and differentiation through CXCL8 and TGF-β1, respectively. These results provide a potential new strategy for improving MSC-mediated therapy.

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Frequency of Effector Memory Cells Expressing Integrin α₄β₇ Is Associated With TGF-β1 Levels in Therapy Naive HIV Infected Women With Low CD4⁺ T Cell Count.

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Frequency of Effector Memory Cells Expressing Integrin α4β7 Is Associated With TGF-β1 Levels in Therapy Naive HIV Infected Women With Low CD4+ T Cell Count.

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Frequency of Effector Memory Cells Expressing Integrin α₄β₇ Is Associated With TGF-β1 Levels in Therapy Naive HIV Infected Women With Low CD4⁺ T Cell Count.