Human Immunodeficiency Virus Type 1 Induces Persistent Changes in Mucosal and Blood γδ T Cells despite Suppressive Therapy

Abstract

␥␦ T cells are primarily found in the gastrointestinal mucosa and play an important role in the first line of defense against viral, bacterial, and fungal pathogens. We sought to examine the impact of human immunodeficiency virus type 1 (HIV-1) infection on mucosal as well as peripheral blood ␥␦ T-cell populations. Our results demonstrate that HIV-1 infection is associated with significant expansion of V␦1 and contraction of V␦2 cell populations in both the mucosa and peripheral blood. Such changes were observed during acute HIV-1 infection and persisted throughout the chronic phase, without apparent reversion after treatment with highly active antiretroviral therapy (HAART). Despite an increase in the expression of CCR9 and CD103 mucosal homing receptors on peripheral blood ␥␦ T cells in infected individuals, mucosal and peripheral blood ␥␦ T cells appeared to be distinct populations, as reflected by distinct CDR3 length polymorphisms and sequences in the two compartments. Although the underlying mechanism responsible for triggering the expansion of V␦1 ␥␦ T cells remains unknown, HIV-1 infection appears to have a dramatic impact on ␥␦ T cells, which could have important implications for HIV-1 pathogenesis.␥␦ T cells are minor constituents in the peripheral blood but provide a sizable contribution to the immune compartment of the gastrointestinal mucosa, likely representing the first defense against pathogens crossing this surface. In the mucosa, they constitute up to 50% of all lymphocytes in the intraepithelial compartment and approximately 10% of lymphocytes in the lamina propria (26, 44). Mucosal ␥␦ T cells are ideally situated to contribute to the earliest stages of the immune response against infection through epithelial surfaces and are believed to link the innate and acquired immune responses. In addition, ␥␦ T cells influence gastrointestinal epithelial cell proliferation and differentiation (27) and development of mucosal immunoglobulin A-producing B cells and play a role in oral tolerance (15).␥␦ T cells recognize soluble protein and nonprotein antigens, though the mechanism by which these antigens are recognized remains enigmatic. Unlike ␣␤ T cells, ␥␦ T cells recognize antigens via their T-cell receptor (TCR) in a major histocompatibility complex (MHC)-independent manner. The ␥␦ TCR recognizes intact proteins in a fashion similar to that in which antibodies recognize antigens. ␥␦ T cells employ a distinct set of variable (V), diversity (D), and joining (J) regions. Though the potential of ␥␦ TCR diversity is, in theory, greater than that of ␣␤ T cells (7), reduced combinatorial somatic recombination results in restricted ␥␦ TCR diversity. Despite a restriction in receptor diversity, the lack of antigenic processing or MHC restriction permits recognition of a wide variety of native and foreign antigens. Though there are six known ␥ and six known ␦ chains, peripheral blood ␥␦ T cells in healthy individuals predominantly express the V␦2 and V␥9 TCR variable segments (8).The physiologic role of ␥␦ T ce...

Candida albicansStimulates IL-23 Release by Human Dendritic Cells and Downstream IL-17 Secretion by Vδ1 T Cells

“…However, the factors that induce and regulate IL-17 production by human Vd1 T cells are not known. Vd1 T cells are expanded in the circulation of patients with HIV infection (25)(26)(27). In this study, we show that C. albicans infection is a major determinant of Vd1 T cell expansions in patients with HIV, and we confirm that C. albicans drives expansion of and IL-17 production by human Vd1 T cells in vitro.…”

“…The IL-23/IL-17 axis is also thought to contribute to immunity against HIV; therefore, stimulation of these pathways may also be of particular benefit to patients coinfected with HIV and C. albicans (38)(39)(40). HIV infects and kills IL-17-secreting CD4 + T cells, but Vd1 T cells are expanded in patients with HIV infection (25)(26)(27). Therefore, Vd1 T cells, which are currently under investigation as effectors in tumor immunotherapy (41), have potential for restoring IL-17 responses in patients with HIV/AIDS.…”

“…They are expanded in the circulation of patients with HIV infection (25)(26)(27). They can kill HIV-infected and -uninfected CD4 + T cells (32,33) and can secrete chemokines that suppress replication of HIV-1 in T cell lines in vitro (34).…”

“…Previous studies have demonstrated that Vd1 T cells are expanded in the circulation of patients with HIV infection (25)(26)(27). We used flow cytometry to determine the percentages of T cells that express Vd1 TCRs in fresh PBMCs from 10 healthy donors, 23 treated HIV-infected subjects without Candida coinfection, and 14 HIV-infected subjects with candidiasis.…”

Effect of Highly Active Antiretroviral Therapy on T-Cell Sub-population Profile in Human Immunodeficiency Virus-1 Infected Patients

“…[12]. ϒδ T cells population are minor constituents in the peripheral blood but provide a high contribution to the immune compartment of the gastrointestinal mucosa [13], likely representing the first defense against pathogens crossing this surface. In the mucosa, they constitute up to 50% of all lymphocytes population and approximately 10% of lymphocytes in the lamina propria [14][15][16].…”