Activation, exhaustion, and persistent decline of the antimicrobial MR1-restricted MAIT-cell population in chronic HIV-1 infection

Abstract

• Antimicrobial CD8 ϩ MAIT cells are activated, exhausted, and progressively and persistently depleted during chronic HIV-1 infection.• This decline in MAIT cell level and function may seriously impair the ability to mount immune responses to bacterial and fungal pathogens. IntroductionHIV-1 infection is associated with a range of pathologic changes to the immune system, including systemic immune activation, CD4 T-cell loss and CD8 T-cell expansion. The state of broad and persistent immune activation develops early during infection, 1,2 contributes to the rapid aging of the immune system seen during chronic progressive HIV-1 disease, and persists despite effective long-term virologic suppression by combination antiretroviral therapy (cART; reviewed in by Deeks, 3 Appay et al, 4 and Desai and Landay 5 ). These pathologic processes lead to the progressive destruction of lymphoid organs and loss of CD4 helper T cells. 6,7 Already during primary infection, HIV-1 depletes intestinal CD4 T cells and disrupts the structure and function of the intestinal immune system. [8][9][10][11][12][13] One consequence of this is increased permeability of the intestinal epithelium with translocation of microbial products into the local tissue, the portal circulation, the liver and eventually into systemic circulation. 14 This process may continue despite effective long-term cART. 15,16 Disruption of immune homeostasis and barrier function at the mucosa is a considerable challenge for the host immune system because the microbial proteins, carbohydrates, and lipids form a range of antigens that will engage innate as well as adaptive immune mechanisms (reviewed by Brenchley and Douek 17 ). Despite considerable advances in the treatment and management of HIV-1 disease, certain infections still present a significant clinical challenge particularly among HIV-infected individuals who are diagnosed at advanced stages, those who lack access to antiretroviral therapy, and those who cannot maintain adherence to therapy and clinical care. [18][19][20] This includes an increased risk of developing bacterial pneumonia even in HIV-1-infected patients with relatively normal CD4 counts, 21 indicating that impaired CD4 T-cell independent control of certain infections still exists even in the context of treated HIV-1 disease. Mucosal-associated invariant T (MAIT) cells are a relatively recently discovered subset of unconventional, innate-like T cells that are highly abundant in mucosal tissues, liver, and peripheral blood. [22][23][24][25] Human MAIT cells express an invariant T-cell receptor (TCR) carrying the V␣7.2 ␣-chain segment, a restricted V␤ repertoire (V␤2 or V␤13), and recognize antigens in complex with the evolutionarily conserved MHC-Ib-related protein (MR1). 24,25 In addition to the V␣7.2 TCR segment, MAIT cells are defined by Submitted July 27, 2012; accepted November 26, 2012. Prepublished online as Blood First Edition paper, December 13, 2012; DOI 10.1182 DOI 10. /blood-2012 The online version of this article contains a data suppleme...

Mucosal-Associated Invariant T Cell Deficiency in Systemic Lupus Erythematosus

“…In contrast, the production of IFN-g was found to be preserved in RA patients. In our in vitro culture system, however, no significant differences were found in IL-17 or IL-4 level between the patients and HCs because of a relatively weak production of these cytokines, which has also been reported in other studies (26,34,39). Similar findings have also been reported in chronically HIV-infected patients.…”

“…In particular, this MAIT cell deficiency was more prominent in CD8 + and DN MAIT cell subsets. These findings have also been previously demonstrated in patients with multiple sclerosis or HIV infection, in whom all the MAIT cell subset levels were reduced (26,34). Thus, reductions in CD8 + and DN subset levels might contribute to circulating MAIT cell deficiencies in SLE and RA patients.…”

“…The observation that circulating MAIT cell numbers are reduced has also been reported in some human diseases, including human HIV infection, multiple sclerosis, and tuberculosis (4,26,34,39). In this study, we found that circulating MAIT cell numbers were reduced in SLE and RA patients.…”

“…2A). As previously observed (2,4,5,26,34), the majority of MAIT cells in blood consisted of CD8 + and DN subsets. Percentages of CD8 + MAIT cell subsets in ab T cells were significantly lower in SLE patients and in RA patients than in HCs (median: 0.…”

“…Similar findings have also been reported in chronically HIV-infected patients. They displayed preserved MAIT cell responses following PMA/IM stimulation, but MAIT cell responses to E. coli were impaired, which were at least partly restored by effective antiretroviral therapy (34).…”