Around three years ago, much excitement was generated by the discovery that a receptor called PD-1 is expressed by T cells that have become exhausted and dysfunctional as a consequence of chronic stimulation. Targeting of PD-1 in the mouse model of persistent LCMV infection was shown to restore a significant degree of T cell function and decrease viremia. Subsequent studies demonstrated that PD-1 expression increases over the course of HIV infection and correlates with other markers of disease progression such as viral load and CD4 T cell counts. As a result of these discoveries, ongoing research in the SIV model is now evaluating whether anti-PD-1 approaches have the potential to enhance immunity against HIV. However, some caveats have also been raised regarding PD-1: it turns out that the molecule is also transiently expressed as a normal consequence of T cell activation, so is not always a marker of exhaustion. It has also been suggested that some exhausted T cells may not express PD-1.
Last Monday in the Journal of Experimental Medicine, Brad Jones and colleagues reported on another receptor that identifies exhausted T cells in HIV infection, and which also may be amenable to therapeutic manipulation (similar data was also reported at the recent AIDS Vaccine 2008 conference by Marilyn Addo from Bruce Walker’s group, see abstract below). The receptor is personably called Tim-3 (an acronym for the more cumbersome full name: T cell immunoglobulin and mucin domain–containing molecule 3). Data from mouse studies indicates that Tim-3 serves an inhibitory role; interactions between Tim-3 and its Star Trek-sounding ligand galectin-9 promotes the death of interferon-gamma-producing, Th1-type CD4 T cells. Furthermore, blocking the interactions of Tim-3 can prevent the acquisition of transplant tolerance. This murine data prompted Jones et al to investigate the role of Tim-3 in people with HIV.
The study found that Tim-3 expression is significantly elevated in people with acute/early and chronic HIV infection compared to both healthy controls and elite controllers (individuals controlling their HIV viral load to low levels without therapy). Tim-3 expression on both CD8 and CD4 T cells correlated positively with viral load levels, and inversely with peripheral blood CD4 T cell counts. Tim-3 expression also correlated significantly with CD38 expression (a marker of immune activation) on both CD8 and CD4 T cell subsets, with many CD38-expressing cells also displaying Tim-3. Further analyses demonstrated that HIV-specific CD8 T cells preferentially expressed Tim-3 compared to CMV-specific responses from the same individual, with the exception of a CMV-specific CD8 T cell response from an individual with an AIDS diagnosis and a CD4 T cell count of 132. High levels of Tim-3 expression by CD8 T cells equated with a complete lack of cytokine production (even interferon-gamma, which many exhausted T cells can continue to make).
To explore the potential for manipulation of Tim-3, an antibody against the receptor was used in an in vitro test of T cell function. Results showed that blocking Tim-3 significantly increased the proliferative capacity of HIV-specific CD8 and CD4 T cells. The researchers also investigated the extent to which PD-1 and Tim-3 were co-expressed by exhausted T cells, finding that while there was some limited overlap, the two receptors defined largely distinct populations.
In discussing their findings, Jones and colleagues highlight the profound extent of Tim-3 expression documented in their subjects and the implications for disease pathogenesis: “We show that in HIV-1 infection, the proportion of CD8+ and CD4+ T cells in peripheral blood that express Tim-3 can reach in excess of 70 and 30%, respectively (in contrast to means of 28.5 and 17.6% in HIV-1–uninfected individuals). As these frequencies exceed the proportion of HIV-1–specific cells in the periphery, suppression of T cell function by Tim-3 likely contributes not only to the loss-of-functional virus-specific responses but also to the impairment of responses to other antigens.” The authors also note that Tim-3 may be a potential therapeutic target, but stress that the same concerns that apply to anti-PD-1 approaches (the potential disinhibition of autoimmune responses) will also apply to anti-Tim-3 therapies, so careful evaluation in animal models will be required before any human studies can be considered.
Published online November 10, 2008
doi:10.1084/jem.20081398
The Journal of Experimental Medicine
ARTICLE
R. Brad Jones1, Lishomwa C. Ndhlovu5, Jason D. Barbour6, Prameet M. Sheth2, Aashish R. Jha5, Brian R. Long5, Jessica C. Wong1, Malathy Satkunarajah3, Marc Schweneker5, Joan M. Chapman5, Gabor Gyenes1, Bahareh Vali2, Martin D. Hyrcza2, Feng Yun Yue1, Colin Kovacs4, Aref Sassi8, Mona Loutfy7, Roberta Halpenny7, Desmond Persad8, Gerald Spotts6, Frederick M. Hecht6, Tae-Wook Chun9, Joseph M. McCune5, Rupert Kaul2, James M. Rini3, Douglas F. Nixon5, and Mario A. Ostrowski1,2,10
1 Department of Immunology, 2 Clinical Sciences Division, 3 Department of Biochemistry, and 4 Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
5 Division of Experimental Medicine and 6 HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94110
7 Canadian Immunodeficiency Research Collaborative, 8 Maple Leaf Medical Clinic, Toronto, ON M5B 1L6, Canada
9 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
10 Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada
Progressive loss of T cell functionality is a hallmark of chronic infection with human immunodeficiency virus 1 (HIV-1). We have identified a novel population of dysfunctional T cells marked by surface expression of the glycoprotein Tim-3. The frequency of this population was increased in HIV-1–infected individuals to a mean of 49.4 ± SD 12.9% of CD8+ T cells expressing Tim-3 in HIV-1–infected chronic progressors versus 28.5 ± 6.8% in HIV-1–uninfected individuals. Levels of Tim-3 expression on T cells from HIV-1–infected inviduals correlated positively with HIV-1 viral load and CD38 expression and inversely with CD4+ T cell count. In progressive HIV-1 infection, Tim-3 expression was up-regulated on HIV-1–specific CD8+ T cells. Tim-3–expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the Tim-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1–specific T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1–associated T cell dysfunction.
Published online November 17, 2008
doi:10.1084/jem.20082429
The Journal of Experimental Medicine
COMMENTARY
TIMs: central regulators of immune responses
David A. Hafler and Vijay Kuchroo
D.A.H. and V.K. are at Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
ABSTRACT
Exhaustion of T cell responses during chronic viral infections has been observed in both mouse and man and has been attributed to up-regulation of PD-1 on the surface of exhausted T cells. In patients with chronic human HIV infection, T cell exhaustion leads to opportunistic infections associated with AIDS. However, not all the exhausted T cells express PD-1, suggesting that other molecules may be involved in the phenotype. A new study now demonstrates a central role for T cell immunoglobulin and mucin domain–containing protein-3 (TIM-3) in T cell exhaustion during chronic HIV infection and suggests that TIM-3 may be a novel therapeutic target in chronic viral diseases.
AIDS Vaccine 2008, Cape Town, South Africa, October 13-16, 2008
Abstract #P15-23
Increased Tim-3 Expression on T Cells in Chronic HIV-1 Infection
MM Addo1, F Wen1, A Meier1, H Streeck1, G Alter1, M Altfeld1, DE Anderson2, DA Hafler2, and BD Walker1
1 Partners AIDS Research Center/MGH/Harvard Medical School, Charlestown, MA, USA; 2Center for Neurologic Diseases/ Brigham and Women’s Hospital/HMS, Boston, MA, USA
Background: Tim-3 is a transmembrane protein member of the TIM (T cell immunoglobulin and mucin domain) family, specifically expressed on differentiated Th1 and not Th2 lymphocytes. Interactions of Tim-3 and its ligand galectin-9 play a role in downregulating Th1 responses and modulating T cell tolerance. Recent data in HIV-1 infection suggests that surface expression of Tim-3 identifies a novel population of anergic T cells and that blockade of the Tim-3 pathway can restore proliferation and cytokine production in HIV-1 specific T cells. However, little is known about Tim-3 expression on monocytes and dendritic cells in HIV-1 infection. Methods: Tim-3 expression was studied on PBMC derived from HIV-1 infected individuals in different stages of HIV-1 infection, including persons with chronic untreated, chronic treated and acute infection, as well as HIV elite controllers and HIV negative controls. Tim-3 expression on T lymphocytes, monocytes, plasmacytoid (pDCs) and myeloid dendritic cells (mDCs) was quantified by multiparameter flowcytometry. Frequencies of Tim-3 expressing cells were correlated to markers of disease progression. Results: Tim-3 expression on CD4 and CD8 T lymphocytes was upregulated in chronic untreated HIV-1 infection. Expression was higher on CD8 compared to CD4 T cells. Interestingly, the Tim-3 expression on CD8 T cells was positively correlated with HIV-1 viral load. Tim-3 expression was also detected on mDCs and pDCs from HIV-1 infected individuals, while the highest expression of Tim-3 was observed on monocytes. However, no statistically significant differences were detected between HIV positive and negative individuals. Conclusion: Taken together these results indicate that Tim-3 is expressed on T cells and antigen presenting cells in HIV-1 infection and its expression on CD8 T cells correlates with markers of disease progression. In light of recent data suggesting that Tim-3 blockade enhances HIV-1 specific immune responses this molecule may hold promise as a potential target for future therapeutic interventions.
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