Abnormal Presence of Semimature Dendritic Cells That Induce Regulatory T Cells in HIV‐Infected Subjects

Abstract

Dendritic cells (DCs), because they orchestrate the immune response to microbes, represent an ideal target for pathogens attempting to evade the immune system. We hypothesized that interactions between human immunodeficiency virus (HIV) and DCs lead to the development of a semimature state, in which DCs migrate to lymph nodes but induce tolerance in T cells, rather than immunity. We found that lymph nodes from untreated HIV-infected subjects contained an abundance of semimature DCs, the disappearance of which correlated with the initiation of highly active antiretroviral therapy (HAART). Such lymph nodes also contained an abundance of T cells that had a regulatory phenotype and that persisted after HAART. Lymph node DCs from untreated HIV-infected subjects cultured with normal allogeneic T cells induced these T cells to adopt the phenotype of regulatory T cells, an ability that was lost after HAART. We conclude that HIV infection correlates with the presence of semimature DCs that stimulate T cell tolerance rather than immunity. These regulatory T cells may contribute to the lack of effective HIV immune responses.

Increased Frequency of Regulatory T Cells Accompanies Increased Immune Activation in Rectal Mucosae of HIV-Positive Noncontrollers

“…This is in agreement with previous studies examining Treg in lymphoid and mucosal tissues of HIV ϩ progressors (3,27,31,53,56,78). We did not observe a corresponding increase in peripheral blood of noncontrollers, in contrast to what has been reported previously (71,78,89).…”

“…85,2011 Treg IN RECTAL MUCOSAE OF HIV NONCONTROLLERS 11431 the regulatory population; alternatively, both populations may be infected and depleted to a similar extent, but Treg may be more quickly replaced. Indeed, multiple mechanisms may influence Treg numbers in the mucosae, including recruitment and trafficking (3,50), increased survival (50,69), active proliferation (3,27), and peripheral conversion of non-Treg into Treg (56). A recent study of SIV-infected rhesus macaques found high levels of HIV DNA present in Treg but low levels of HIV RNA, indicating Treg were permissive to viral entry and integration, but not productively infected.…”

Parallel Loss of Myeloid and Plasmacytoid Dendritic Cells from Blood and Lymphoid Tissue in Simian AIDS

“…In our study the Lin Ϫ HLA-DR mod cells did not acquire CD11c or CD123 expression after 24 h of culture, although it is conceivable that a longer period of culture would promote their differentiation. It is also interesting to note that the lymph nodes of HIV-infected subjects were found to contain an abundance of semimature DC defined as being Lin Ϫ CD83 ϩ IL-12 Ϫ , which induced allogeneic T cells to adopt a regulatory T cell phenotype (56). The low CD86 and lack of CD80 expression of the Lin Ϫ HLA-DR mod CD11c Ϫ CD123 Ϫ cells in the lymph nodes of monkeys with AIDS are consistent with these cells being regulatory rather than immunostimulatory DC.…”

Natural Regulatory T Cells and Persistent Viral Infection

“…In support of this hypothesis, lymph nodes from untreated HIV-infected subjects contained an abundance of immature DC, the loss of which correlated with the initiation of HAART. Lymph node DC from untreated HIV-infected subjects cultured with normal allogeneic T cells induced these T cells to adopt the phenotype of Treg, an ability of DC that was lost after HAART (76). Indoleamine 2,3-dioxygenase (IDO)-mediated tryptophan catabolism in DC can induce a Treg phenotype in Th cells (36), providing an additional mechanism for DC-mediated Treg expansion/conversion during viral infection.…”