HIV-1-Induced Impairment of Dendritic Cell Cross Talk with γδ T Lymphocytes

Abstract

The interplay between dendritic cells (DC) and ␥␦ ⌻ lymphocytes represents a network of paracrine and cell contact interactions important for an integrated immune response to pathogens. HIV-1 infection dramatically affects the number and functions of both cell populations, and DC/␥␦ ⌻ cell cross talk may represent a target of virus-induced immune escape. We investigated whether HIV-exposed DC could deliver aberrant signals to interacting ␥␦ ⌻ cells. Here we report that the interaction of human ␥␦ T lymphocytes with HIV-1-exposed autologous monocyte-derived DC, but not direct exposure to the virus, impairs lymphocyte expansion and gamma interferon (IFN-␥) production in response to phosphoantigens. This effect is independent of virus strain and occurred in 55% of the donors analyzed. The donor-dependent variation observed relies on the responsiveness of DC to HIV-1 and is strictly related to the capacity of the virus to suppress the maturation-induced expression of interleukin 12 (IL-12). In fact, ␥␦ T cell response to phosphoantigens is almost completely recovered when this cytokine is exogenously added to the DC/lymphocyte cocultures. Interestingly, we show that ␥␦ T lymphocytes are recruited by HIV-1-exposed DC through a CCR5-mediated mechanism and exert a CCL4-mediated control on virus dissemination within DC and susceptible CD4 ؉ T lymphocytes. These results demonstrate an association between HIV-induced DC dysfunction and alterations of ␥␦ T cell responses. The aberrant cross talk between these two cell populations may contribute to the pathogenesis of HIV infection by further reducing the strength of antiviral immune response. IMPORTANCEThis study provides new evidence on the mechanisms exploited by HIV-1 to evade the host immune response. We report that HIV-1 impairs the cross talk between DC and ␥␦ T lymphocytes, by reducing the capacity of DC to promote functional ␥␦ T cell activation. Interestingly, the virus does not per se interfere with ␥␦ T cell activation, thus highlighting the key role of early DC-HIV-1 interaction in this phenomenon. Furthermore, the results obtained unravel the novel role of ␥␦ T cells in controlling HIV-1 dissemination within the DC population as well as virus transfer to susceptible CD4 ؉ T lymphocytes. The interactions of DC with innate lymphocytes represent a major control mechanism for an integrated immune response to infection. Understanding how HIV-1 harnesses these pathways may provide important insights on the pathogenesis of disease and offer new opportunities for therapeutic interventions.

Coronavirus infections and immune responses

“…In addition, HIV‐1 attenuates the major histocompatibility antigen I (MHC I) on the surface of DCs, thereby reducing the ability of DCs to present the viral antigens. HIV‐1 infection enhances the expression of DC‐specific intercellular adhesion molecule‐3‐grabbing nonintegrity (DC‐SIGN), thus inhibiting CC chemokine receptor 7 (CCR7) and MHC‐II, which are important receptors of DC homing 58,59 . These results indicate that virus infection interferes with the differentiation and function of DCs, hinders the subsequent adaptive immune response mediated by DCs, and makes the virus evade the adaptive immune response of the host successfully.…”

γδ T‐cell responses during HIV infection and antiretroviral therapy

“…43,84 Vd2 T cells can be recruited to HIV-infected DCs via CCL4 production, where they control viral replication and reduce HIV transmission to bystander CD4 + T cells. 61 b-Chemokine production by both Vd1 85 and Vd2 86 cells can block HIV infection of target cells. However, whether this in vitro activity translates into in vivo control of viremia remains unresolved.…”

“…At the simplest level, methods for recovering Vd2 responses to phosphoantigen among HIV-infected donors include cytokine supplementation with IL-18 117 or IL-12. 61 Such an approach may improve Vd2mediated immune responses against…”

Mucosal and Systemic γδ+ T Cells Associated with Control of Simian Immunodeficiency Virus Infection

“…Activated γδ T cells can acquire B cell helper activity and thus might modify adaptive immunity by regulating antibody responses (11, 12). Interaction of γδ T cells with dendritic cells also impacts responses of both cell types (13). …”