The Tim-3 receptor has been implicated as a negative regulator of adaptive immune responses and has been linked to T-cell dysfunction in chronic viral infections, such as HIV. Blocking Tim-3 has been proposed as a potential therapeutic intervention in HIV infection. However, a more detailed characterization of Tim-3 expression in the presence of HIV is required before such strategies can be considered.
In this study, we investigate Tim-3 expression on innate immune cell subsets in chronic HIV-infected individuals pretherapy and posttherapy.
We report that, pretherapy, HIV infection is associated with elevated levels of Tim-3 on resting innate lymphocytes (NK, NKT, and γδ T cells), but not resting monocytes. In the absence of HIV infection, stimulation with an inflammatory stimulus resulted in decreased Tim-3 on monocytes and increased Tim-3 on NK, NKT, and γδ T cells. However, innate cells from HIV-infected donors were significantly less responsive to stimulation. Six months of combination antiretroviral therapy (cART) restored Tim-3 levels on resting NK cells but not NKT or γδ T cells. The responses of all subsets to inflammatory stimuli were restored to some extent with cART but only reached HIV-negative control levels in monocytes and NK cells.
These results demonstrate that, during HIV infection, Tim-3 expression on innate cells is dysregulated and that this dysregulation is only partially restored after 6 months of cART. Our findings suggest that Tim-3 is differentially regulated on innate immune effector cells, and have direct implications for strategies designed to block Tim-3–ligand interactions.
*SAR Laboratories, Sandra Rotman Centre for Global Health, UHN-Toronto General Hospital, Toronto, ON, Canada;
†Department of Medicine, Division of Infectious Diseases, University of Toronto, Toronto, ON, Canada;
‡Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Canada;
§Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada;
‖Department of Immunology, University of Toronto, Toronto, Canada;
¶Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Canada; and
#Maple Leaf Medical Clinic, Toronto, Canada.
Correspondence to: Lena Serghides, PhD, SAR Laboratories, Sandra Rotman Centre for Global Health, MaRS, TMDT, Suite 10-359, 101 College Street, Toronto, ON M5G 1L7, Canada (e-mail: firstname.lastname@example.org).
C. A. M. F. was supported by a CTN/OHTN postdoctoral fellowship, L. S. is supported by an OHTN Junior Investigator Development Award, K. C. K. is supported by a Canada Research Chair in Molecular Parasitology. This work was supported by CIHR operating grants (MOP-13721 and 115160) to K. C. K. and L. S., and a CIHR catalyst (CI1-103128) grant to L. S. CTN provided funding for patient enrolment.
The authors have no conflicts of interest to disclose.
K. C. Kain and L. Serghides have contributed equally as senior authors.
Received October 10, 2012
Accepted January 02, 2013