Enhanced Gut-Homing Dynamics and Pronounced Exhaustion of Mucosal and Blood CD4+ T Cells in HIV-Infected Immunological Non-Responders.

Kristina Berg Lorvik,Malin Holm Meyer-Myklestad,Charlotte Handeland,Anne Margarita Dyrhol-Riise,Dag Kvale,Asle Wilhelm Medhus,Dag Henrik Reikvam,Marius Lund-Iversen,Birgitte Stiksrud,Kjetil Taskén,Kushi Kushekar

doi:10.3389/fimmu.2021.744155

Kristina Berg Lorvik, Malin Holm Meyer-Myklestad + Show 9 more

Open Access

https://doi.org/10.3389/fimmu.2021.744155

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Abstract

Immunological non-responders (INR), a subgroup of people living with HIV (PLHIV) who fail to restore CD4+ T cell numbers upon effective antiretroviral treatment, have impaired gut mucosal barrier function and an inferior clinical prognosis compared with immunological responders (IR). The contribution of gut-homing and exhaustion of mucosal T cells to the INR phenotype was previously unknown. Flow cytometry analysis of mononuclear cells from peripheral blood and ileal and colonic lamina propria showed that INR had higher fractions of gut-homing CD4+ T cells in blood compared with IR. In addition, gut-homing cells were more likely to display signs of exhaustion in INR. The increased CD4+ T cell exhaustion in INR was ubiquitous and not restricted to subpopulations defined by activation, differentiation or regulatory T cell markers. In INR, colon CD4+ T cell exhaustion correlated negatively with the fraction of CD4+ T cells in the same compartment, this was not apparent in the ileum. The fraction of exhausted mucosal CD4+ T cells correlated with I-FABP and REG3α, markers of enterocyte damage. We conclude that alterations of gut-homing and exhaustion of T cells may contribute to impaired gut immune and barrier functions associated with immunological non-response in PLHIV.

Highlights

The gastrointestinal tract is the major site of HIV infection and replication
All participants were Caucasian men matched by age, and people living with HIV (PLHIV) were in addition matched on nadir CD4 count
As we demonstrated that Immunological non-responders (INR) had more exhausted programmed death-1 (PD1)+ TIGIT+ CD4+ T cells in the gut, we wanted to investigate whether PD-ligand 1 (PD-L1) was expressed in the gut mucosa

Summary

Introduction

The gastrointestinal tract is the major site of HIV infection and replication. Early after infection there is a massive depletion of mucosal CD4+ T cells and a disruption of the epithelial layer that serves as a protective barrier against luminal content [1, 2]. The consequence is typically translocation of microbial products from the gut lumen into the lamina propria and gut-associated lymphoid tissue (GALT), with a subsequent systemic inflammation characterized by an increase in inflammatory mediators and activation of immune cells [3,4,5]. Upon effective antiretroviral therapy (ART), circulating CD4+ T cells are restored and the level of systemic inflammation is reduced, but not normalized. The restoration of gut CD4+ T cells is slower than in the peripheral blood and it is under debate how effective ART is in restoring mucosal immunity [6]. Exhaustion, and differentiation of CD4+ T cells are factors that could hamper normalization of the mucosal immunity in PLHIV [8,9,10,11]

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