Double-negative T cells during HIV/SIV infections

Abstract

Purpose of the review This review summarizes the role of CD3+CD4−CD8− double-negative T cells, which have both regulatory and helper T cell function and may have the potential to compensate for the reduced levels of CD4+ T cells during SIV/HIV infection. Recent findings Double-negative (DN) T cells have been characterized in several human diseases and in murine models of autoimmunity and transplantation, where they exhibit both immunoregulatory and helper T cell-like function. During the natural nonpathogenic SIV infection of African nonhuman primates, the lack of clinical disease progression is associated with the presence of DN T cells that maintain helper T cell functions while remaining refractory to viral infection. Moreover, DN T cells may compensate for very low levels of CD4+ T cells observed in a cohort of sooty mangabeys that have been infected with SIV for over 10 years and have remained free of clinical disease manifestations associated with AIDS. These studies identify a potential for DN T cells to provide critical helper function during HIV infection. Summary DN T cells with some CD4+ T cell functions are associated with a nonpathogenic outcome during SIV infection and represent a potential immune therapeutic target in HIV-infected patients.

The Contribution of Non-Conventional T Cells and NK Cells in the Mycobacterial-Specific IFNγ Response in Bacille Calmette-Guérin (BCG)-Immunized Infants

“…Similarly in mice, DN T cells kill CD4 T cells, B cells and NK cells and down-regulate co-stimulatory molecules on mature dendritic cells thus contributing to immune tolerance [28]. In simian immunodeficiency virus infection, DN T cells develop CD4 T cell functions that parallel the loss of CD4 T cells and protect against viral dissemination [29]. DN T cells are also involved in the mycobacterial-specific immune response in mice [30,31] and develop a memory phenotype, potentially contributing to effective protection [30].…”

Multifunctional Double-negative T Cells in Sooty Mangabeys Mediate T-helper Functions Irrespective of SIV Infection

“…Although the precise path of peripheral DN T cell development is not known, there are three models that have been proposed to explain how these cells arise and are maintained in the periphery [17]. One model proposes that immature DN thymocytes acquire expression of the T-cell receptor (TCR), bypass the subsequent double-positive (DP) and single-positive (SP) stages of classical T cell maturation, and migrate directly to the periphery.…”

“…A second model suggests that a pre-T cell experiences all the normal development in the thymus but due to strong TCR∶MHC binding (sufficient to evade apoptosis) during negative selection, does not experience the CD4 or CD8 single positive stage. A third model suggests T cells proceeding all the way to the single-positive CD4 T cell, then experiencing a subsequent down-modulation of expression of the CD4 mRNA transcription and surface protein expression (reviewed in [17]). …”

Double Negative (DN) αβ T Cells: misperception and overdue recognition

“…42 In addition, nDN T cells are reported to be an important source of infectious virus in HIV patients. 43, 44 DN T cells also comprise a high percentage (20–25%) of αβ T cells in kidneys of mice 37, 38 and in humans (Martina et al unpublished results). By analogy, it is likely that nDN T cells are enriched in other non-lymphoid organs.…”