Regulatory T-Cell Markers, Indoleamine 2,3-Dioxygenase, and Virus Levels in Spleen and Gut during Progressive Simian Immunodeficiency Virus Infection

Abstract

High levels of viral replication occur in gut-associated lymphoid tissue (GALT) and other lymphoid tissues (LT) since the early phase of human/simian immunodeficiency virus (HIV/SIV) infection. Regulatory T cells (Treg), a subset of immunosuppressive T cells expressing CTLA-4 and the FoxP3 transcription factor, accumulate in LT during HIV/SIV infection. Here we show that FoxP3 and CTLA-4 mRNA are increased in leukocytes from the spleens, lymph nodes (LN), and mucosal sites of chronically SIV-infected macaques with high viremia (SIVHI) compared to animals with low viremia (SIVLO). FoxP3 and CTLA-4 correlated with SIV RNA levels in tissues; SIV virus levels in the spleen, inguinal LN, mesenteric LN, colon, and jejunum directly correlated with the plasma virus level. Importantly, CTLA-4 and FoxP3 mRNA were predominantly increased in the CD25− subpopulation of leukocytes from SIVHI, further challenging the classical definition of Treg as CD4+ CD25+ T cells. Similar to CTLA-4 and FoxP3, expression of indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme induced by Treg in antigen-presenting cells, was increased in the spleens, mesenteric LN, colons, and jejuna from SIVHI compared to SIVLO and directly correlated to SIV RNA in the same tissues. Accordingly, plasma kynurenine/tryptophan, a marker for IDO enzymatic activity, was significantly higher in SIVHI compared to SIVLO and correlated with plasma viral levels. Increased Treg and IDO in LT of SIV-infected macaques may be the consequence of increased tissue inflammation and/or may favor virus replication during the chronic phase of SIV infection.

Expansion of FOXP3+ CD8 T Cells with Suppressive Potential in Colorectal Mucosa Following a Pathogenic Simian Immunodeficiency Virus Infection Correlates with Diminished Antiviral T Cell Response and Viral Control

“…It has been shown that SIV/HIV induces increased expression of IDO, an immunosuppressive enzyme that is capable of inducing CD4 Tregs (58). This increase in IDO expression is detected in lymphoid and intestinal mucosal tissues as early as 7 d after SIV infection (30,31,37,59). Similarly, TGF-b has also been shown to induce expression of FOXP3 by mouse naive CD8 + T cells following stimulation with anti-CD3 and anti-CD28 (60).…”

Immune Activation Driven by CTLA-4 Blockade Augments Viral Replication at Mucosal Sites in Simian Immunodeficiency Virus Infection

“…Studies on gene expression in tissue RNA demonstrate a significant increase in the expansion of CTLA-4, IDO, and TGF-␤ in chronically infected macaques (19,23). However, transient expression of these markers by newly activated T cells, not only by T reg , precludes an accurate assessment of the importance of T reg in AIDS pathogenesis using gene expression or phenotypic markers.…”

“…Some reports conclude that T reg or T reg -associated markers are decreased in blood of HIV-1-infected individuals while others indicate an increase of T reg in tissues (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Even during the stages of SIV infection, the dynamics of T reg distribution are unclear.…”

“…ϩ T cells at mucosal sites IDO, an enzyme that converts tryptophan into kynurenine and halts T cell proliferation, is expressed at high level in tissues of HIV/ SIV-infected hosts (19,20,38). Because IDO is induced by the engagement of CTLA-4 expressed on T reg or activated T cells to the CD80 or CD86 molecules on the surface of APC (15), analysis of IDO level provided an opportunity to assess whether the high level of IDO in SIV infection could be lowered by CTLA-4 blockade.…”

Primary infection with simian immunodeficiency virus: plasmacytoid dendritic cell homing to lymph nodes, type I interferon, and immune suppression

“…We recently described the dynamics of adaptive immunity in these macaques 33,46 and showed a transient expansion of CD25 bright CD8 ϩ T cells, which express FoxP-3 and CTLA-4-2 molecules expressed by regulatory T cells (Tregs)-9 to 35 days after infection. 33 Because IDO was recently shown to be induced by HIV in pDCs in vitro 21 and to correlate with viral load in HIV infection, 29 and because pDCs expressing IDO activate Tregs in a mouse tumor model, 47 we searched for the correlation between IDO activity and FoxP3 ϩ CD8 ϩ T-cell subset expansion in vivo. IDO activity correlated not only with plasma viral load (Spearman rank correlation P ϭ .0005, ϭ 0.84) but also with transient expansion of the FoxP3 ϩ CD25 ϩ CD8 ϩ T-cell subset (P ϭ .0005, ϭ 0.85; Figure 6A,B).…”