Increased numbers of circulating CD8+ T cells during HIV-1 infection is associated with increased morbidity and mortality. Consequently, there is great interest in understanding the mechanisms that drive CD8+ T cell expansion and activation in HIV-1-infected individuals. Younes and colleagues at Case Western Reserve University now shed light on the molecular features of CD8+ T cell expansion during HIV-1 infection. Using antibody- and sequencing-based approaches, the authors determined that cells isolated from expanded CD8+ T cell populations express a wide range of T cell receptors (TCRs). In fact, the TCR diversity of the expanded CD8+ T cell population resembled the clonal diversity of TCRs observed in resting CD8+ T cell populations. This data supports the prevailing theory that expansion of CD8+ T cells in chronic HIV-1 infection is due to indiscriminate activation of the immune system (so-called bystander activation) and not due to expansion of HIV-1-reactive clones. Treatment of peripheral blood mononuclear cells (PBMCs) with the cytokine IL-15 promoted CD8+ T cell activation and cycling, suggesting that IL-15 may be involved in stimulating bystander activation in vivo. Younes and colleagues isolated lymph nodes (LNs) from healthy and HIV-1-infected individuals and, using immunohistochemical staining, revealed that IL-15 is highly expressed in LNs of untreated HIV-1 infection. Moreover, the expression of IL-15 positively correlated with the numbers of circulating CD8+ T cells in HIV-1-infected individuals. Taken together, the data indicate that the expansion of CD8+ T cells in chronic HIV-1 infection is a consequence of IL-15-linked bystander activation. The accompanying image shows IL-15 (brown) and hematoxylin (blue) staining of lymph nodes obtained from healthy (left panel), untreated HIV-1-infected (middle panel), and treated HIV-1-infected (right panel) individuals. Note the prominent IL-15 staining in the LNs from the untreated HIV-1-infected individual.
In HIV-1–infected patients, increased numbers of circulating CD8+ T cells are linked to increased risk of morbidity and mortality. Here, we identified a bystander mechanism that promotes CD8 T cell activation and expansion in untreated HIV-1–infected patients. Compared with healthy controls, untreated HIV-1–infected patients have an increased population of proliferating, granzyme B+, CD8+ T cells in circulation. Vβ expression and deep sequencing of CDR3 revealed that in untreated HIV-1 infection, cycling memory CD8 T cells possess a broad T cell repertoire that reflects the repertoire of the resting population. This suggests that cycling is driven by bystander activation, rather than specific antigen exposure. Treatment of peripheral blood mononuclear cells with IL-15 induced a cycling, granzyme B+ phenotype in CD8+ T cells. Moreover, elevated IL-15 expression in the lymph nodes of untreated HIV-1–infected patients correlated with circulating CD8+ T cell counts and was normalized in these patients following antiretroviral therapy. Together, these results suggest that IL-15 drives bystander activation of CD8+ T cells, which predicts disease progression in untreated HIV-1–infected patients and suggests that elevated IL-15 may also drive CD8+ T cell expansion that is linked to increased morbidity and mortality in treated patients.
Souheil-Antoine Younes, Michael L. Freeman, Joseph C. Mudd, Carey L. Shive, Arnold Reynaldi, Soumya Panigrahi, Jacob D. Estes, Claire Deleage, Carissa Lucero, Jodi Anderson, Timothy W. Schacker, Miles P. Davenport, Joseph M. McCune, Peter W. Hunt, Sulggi A. Lee, Sergio Serrano-Villar, Robert L. Debernardo, Jeffrey M. Jacobson, David H. Canaday, Rafick-Pierre Sekaly, Benigno Rodriguez, Scott F. Sieg, Michael M. Lederman