Daniel Kaufmann’s study regarding CTLA-4 expression on HIV-specific CD4 T cells, which was presented at the Keystone meeting back in March (see this prior posting for a detailed description of the study findings), has now been published in the advance online section of Nature Immunology (UPDATE 10/20/07: the Nature Immunology website has made the full text of the paper available free of charge). Mass General Hospital also issued a press release highlighting the publication of the paper. Expression of CTLA-4 can be associated with T cell dysfunction and anti-CTLA-4 strategies are being explored in people with cancer to ascertain if tumor-specific T cell responses can be beneficially enhanced. Kaufmann and colleagues suggest that perhaps these strategies should also be studied in the context of anti-HIV immunotherapy.
There are some broad similarities between CTLA-4 and PD-1, another molecule upregulated in the context of T cell dysfunction (specifically, a type of dysfunction called exhaustion), but PD-1 levels are typically elevated on HIV-specific CD4 and CD8 T cells while Kaufmann’s study shows that elevated CTLA-4 expression is restricted to HIV-specific CD4 T cells.
Another recent paper on PD-1 expression in HIV spotlights some of the potential confounding issues involved in exploring the role of these molecules in T cell dysfunction. The study shows that PD-1 can be transiently expressed during normal T cell activation and therefore researchers need to carefully distinguish between PD-1 expression as a marker of T cell activation and PD-1 expression as a marker of T cell exhaustion. The study authors note that the correlations between PD-1 expression and viral load that have been reported previously may relate to the close correlation they observed between CD38 (a T cell activation marker) and PD-1 expression.
Nat Immunol. 2007 Sep 30; [Epub ahead of print]
Kaufmann DE, Kavanagh DG, Pereyra F, Zaunders JJ, Mackey EW, Miura T, Palmer S, Brockman M, Rathod A, Piechocka-Trocha A, Baker B, Zhu B, Le Gall S, Waring MT, Ahern R, Moss K, Kelleher AD, Coffin JM, Freeman GJ, Rosenberg ES, Walker BD.
In progressive viral infection, antiviral T cell function is impaired by poorly understood mechanisms. Here we report that the inhibitory immunoregulatory receptor CTLA-4 was selectively upregulated in human immunodeficiency virus (HIV)-specific CD4(+) T cells but not CD8(+) T cells in all categories of HIV-infected subjects evaluated, with the exception of rare people able to control viremia in the absence of antiretroviral therapy. CTLA-4 expression correlated positively with disease progression and negatively with the capacity of CD4(+) T cells to produce interleukin 2 in response to viral antigen. Most HIV-specific CD4(+) T cells coexpressed CTLA-4 and another inhibitory immunoregulatory receptor, PD-1. In vitro blockade of CTLA-4 augmented HIV-specific CD4(+) T cell function. These data, indicating a reversible immunoregulatory pathway selectively associated with CD4(+) T cell dysfunction, provide a potential target for immunotherapy in HIV-infected patients.
AIDS. 2007 Oct 1;21(15):2005-2013.
PD-1 expression on human CD8 T cells depends on both state of differentiation and activation status.
Sauce D, Almeida JR, Larsen M, Haro L, Autran B, Freeman GJ, Appay V.
OBJECTIVE AND DESIGN:: PD-1 expression on HIV-specific CD8 T cells was recently reported to reflect functional exhaustion, resulting in uncontrolled HIV-1 replication. Assessing PD-1 expression on T cells may be highly relevant in T-cell immunology and vaccine monitoring. However, this requires us to gain further insights into the significance of PD-1 expression on CD8 T cells in humans. METHODS:: We performed a detailed analysis of PD-1 expression pattern on various CD8 T cell subsets from healthy or HIV infected donors. RESULTS:: PD-1 expression has two facets in vivo. On the one hand, it is linked to T-cell differentiation: PD-1 is up-regulated on early/intermediate differentiated subsets, which include HIV and Epstein-Barr virus-specific CD8 T-cell populations, but is down-regulated during late stages of differentiation. On the other hand, it is linked to T-cell activation: on PD-1 positive cells, PD-1 over-expression occurs along with the up-regulation of activation markers such as CD38 or HLA-DR. CONCLUSIONS:: PD-1 expression on CD8 T cells, including those specific for HIV, can be related both to their differentiation stage and their activation status. It is important to consider these findings when assessing the expression of PD-1 on T cells.
Comments