Severe functional impairment and elevated PD‐1 expression in CD1d‐restricted NKT cells retained during chronic HIV‐1 infection

Abstract

Invariant CD1d-restricted NKT cells play important roles in regulating both innate and adaptive immunity. They are targeted by HIV-1 infection and severely reduced in number or even lost in many infected subjects. Here, we have investigated the characteristics of NKT cells retained by some patients despite chronic HIV-1 infection. NKT cells preserved under these circumstances displayed an impaired ability to proliferate and produce IFN-c in response to CD1d-restricted lipid antigen as compared with cells from uninfected control subjects. HIV-1 infection was associated with an elevated expression of the inhibitory programmed death-1 (PD-1) receptor (CD279) on the CD4 À subset of NKT cells. However, blocking experiments indicated that the functional defects in NKT cells were largely PD-1-independent. Furthermore, the elevated PD-1 expression and the functional defects were not restored by anti-retroviral treatment, and the NKT cell numbers in blood did not recover significantly in response to treatment. The functional phenotype of NKT cells in these patients suggests an irreversible immune exhaustion due to chronic activation in vivo. The data demonstrate a severe functional impairment in the remaining NKT-cell compartment in HIV-1-infected patients, which limits the prospects to mobilize these cells in immunotherapy approaches in patients.Key words: CD1d . HIV . Human . NKT cells . Programmed death-1 IntroductionNKT cells are unconventional T lymphocytes that operate on the border between the innate and the adaptive immune systems, and have some characteristics of both systems [1][2][3]. Their invariant TCR recognizes lipid and glycolipid antigens in complex with CD1d molecules expressed primarily on DC, monocytes and B lymphocytes [4][5][6]. In line with their capacity to influence both innate and adaptive immunity, they are believed to be important regulatory cells in diverse settings of autoimmunity [7], cancer [8], allergy [9] and infectious diseases [10]. The observation that NKT cells are efficiently targeted and lost in HIV-1 infection was therefore of significant interest [11][12][13], as their loss may play a role in the severe immune dysregulation and chronic immune activation that is characteristic of this infection [14][15][16][17][18].Human NKT cells have a constitutive memory T-cell-like phenotype, which includes expression of HIV-1 co-receptors CCR5 and CXCR4 [11,13,19], and direct infection may be 902a primary cause of their loss in infected subjects. However, there are several subsets of NKT cells that differ in their expression of surface receptors. CD4 functions as a co-receptor in NKT cells [20,21], and also defines a functionally distinct subset that usually represents roughly half of cells [22][23][24]. Although the CD4 1 subset is more susceptible to HIV-1 infection in vitro and probably also in vivo [11,13], loss of NKT cells in patients may not be restricted to the CD4 expressing cells [11,12,25]. The recovery of NKT cells in patients starting anti-retroviral treatment (ART) is probably ...

NKT cells: Friend or foe during viral infections?

“…Most iNKT cells from HIV-1-infected individuals strongly express the Fas receptor, suggesting that Fasmediated apoptosis might contribute to iNKT-cell depletion [21]. During chronic HIV-1 infection, iNKT cells show persistent severe functional impairment and elevated PD-1 expression [23]. Note that antiretroviral therapy only enhances the frequency of circulating iNKT cells when IL-2 is co-administered [24].…”

PD-1hi Identifies a Novel Regulatory B-cell Population in Human Hepatoma That Promotes Disease Progression

“…Blocking the interaction between PD-1 and PD-L1 can restore T-cell function and result in tumor regression in both humans and mice (6)(7)(8)(9). Nevertheless, it should be emphasized that, in addition to being expressed on exhausted T cells, PD-1 can be rapidly upregulated on B cells, natural killer T cells, monocytes, and dendritic cells in infl amed tissues (10)(11)(12)(13), suggesting that PD-1-associated cancer therapy targets not only T cells but also the whole immune system. Thus, evaluating PD-1 expression and function in non-T-cell leukocyte infi ltrate is essential for understanding the roles and potential suppressive mechanisms of PD-1 in tumor immunopathogenesis.…”

Host Immune System Abnormalities Among Patients with Human T-Lymphotropic Virus Type 1 (HTLV-1) - Associated Disorders

“…HIV-1-infected subjects have fewer iNKT cells in their peripheral blood than healthy donors (Sandberg et al, 2002;van der Vliet et al, 2002). The proliferative potential and INFproduction of residual iNKT cells are impaired in HIV-1-infected individuals (Moll et al, 2009); likewise, patients with HTLV-1-associated disorders have a decreased frequency of iNKT cells in their peripheral blood . Interestingly, in contrast to patterns observed in HIV-1 infections, HTLV-1 infection leads to preferential decreases of CD4 -iNKT cells .…”