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CD4 effector memory T cells connected to death in veterans living with HIV..... "suggest an accelerated aging of the immune system, and an increase in this particular risk factor for death"
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Wyatt McDonnell
Vanderbilt University
Aging Workshop: Exhausted & Depleted T Cells in HIV+ Cause Premature Aging & Comorbidities & Frailty Memory loss: T cell subsets associated with mortality in HIV+ and HIV- veterans - (09/18/18)
Researchers from Vanderbilt University, the University of Vermont, and Yale University reported for the first time an association between a select subset of CD4 T cells and the risk of all-cause mortality in HIV+ veterans at the 9th International HIV and Aging Workshop.
T lymphocytes, or T cells, comprise one part of the adaptive immune system-the part of the immune system that develops specific responses to pathogens that the body encounters over time. These responses are developed in a time-dependent fashion, and T cells can be split into different "compartments" based on how young they are, how recently they have seen their target, how they function, and certain surface markers displayed on the surface of the cell.
In this study, McDonnell and colleagues used a technology called flow cytometry to measure levels of 5 major types of CD4+ and CD8+ T cells from 2300 HIV+ and HIV-negative participants in the Veterans Aging Cohort Study. The cells were donated in 2005-2007, and the investigators determined all deaths occurring through 2015. The group examined 5 types of T cells in both the CD8+ and CD4+ T cell compartments: naïve T cells, "activated" T cells, central memory T cells, effector memory T cells, and effector memory revertant T cells (TEMRA cells). Naïve T cells are those that have not yet found their target. Activated T cells express proteins to actively kill their target in the body, while memory cells are those that stand ready to respond to previous threats if they reappear. Finally, the TEMRA population is a unique cell type that has properties of both the memory cells and features of the naïve cells.
These researchers looked at two definitions of TEMRA cells, the first including the positivity for the differentiation marker CD57 and negativity of CD28, and the second including negativity of the differentiation marker CD27. Consensus as to what these markers mean in terms of the function of these T cells has not yet been reached in the immunology community, particularly with regard to the CD57 marker. CD57 has been interpreted both as a marker of immune "senescence" (where cells bearing CD57 are thought to be less capable of responding to their target), but also as a marker of cells that have seen their target repeatedly (studies have also indicated that CD57+ cells are just as capable of dividing, killing, and functioning as their CD57- peers).
Immune senescence is a unique phenomenon that occurs with age, but also in response to chronic inflammation. Repeated and chronic stimulation of the immune system makes it less and less apt to respond to threats effectively, a phenomenon sometimes referred to as 'inflammaging' as such inflammation can age the immune system prematurely. As chronic inflammation is a hallmark of chronic HIV infection, it is perhaps unsurprising that T cells bearing CD57 have been reported to be higher in PLWH in comparison to the general population. However, one of the strengths of the design of the veteran cohort analyzed by McDonnell et al. is that virally suppressed and viremic PLWH were recruited in addition to HIV-negative individuals. Importantly, this cohort was also designed to match individuals within these three groups across their age, gender, race, and other clinical risk factors such as cardiovascular disease. This allowed McDonnell and colleagues to look at the differences between these types of T cells while accounting for commonly confounding parameters that can make comparison of PLWH and HIV- individuals challenging.
McDonnell et al. used individual time-to-event models (also called Cox models) for each T cell subset as measured in approximately 2300 veterans, where the question being tested was whether or not the proportion of each T cell subset was significantly associated with death over time in PLWH or in HIV- veterans. The models were adjusted for age, race, sex, and antiretroviral therapy.
As reported previously, these researchers identified that higher levels of naïve T cells were protective against mortality, while activated CD8+ and CD4+CD38+ were predictive of mortality in HIV+ veterans but not HIV- veterans.
The key and novel finding of this study pinpointed CD4+ TEMRA cells as being predictive of mortality in HIV+ veterans and to a lesser extent in HIV- veterans. McDonnell noted that this could have been due to the smaller number of HIV- veterans whose samples were studied in this cohort. The research team also found that these TEMRA cells were associated with mortality using two different surface marker combinations.
When the research team looked further into these CD4 TEMRA cells, they found that HIV+ veterans had two-folder higher levels of CD4 TEMRA cells regardless of age when looking at veterans younger than 45, 45-55 years old, and older than 55. They also found that HIV+ veterans with suppressed HIV (viral load < 500) had lower levels of CD4 TEMRA cells than viremic HIV+ veterans. While the relationship between CD4 TEMRA cells and mortality was more clear in PLWH, the two-fold higher levels of these TEMRA cells regardless of age seems to suggest an accelerated aging of the immune system, and an increase in this particular risk factor for death.
McDonnell also noted a previously reported link between CD4 TEMRA cells and cytomegalovirus (CMV), a common human herpesvirus that is ubiquitous in PLWH. "Our research team recently completed measurements of the B cell response, or titer, against CMV in this cohort, and we look forward to investigating whether the association with CD4 TEMRA and CMV serostatus is replicable in HIV+ individuals. We also plan to examine the interaction between CMV titer, CD4 TEMRA, and mortality as part of these upcoming studies. Given the known relationship between being CMV-positive and higher levels of these CD4 TEMRA cells in the general population, we are particularly interested in seeing whether or not CMV specifically explains why these cells were predictive of mortality in both PLWH and HIV- individuals."
In conclusion, this study identified a strong association between a novel T cell type and mortality in HIV+ veterans. McDonnell and colleagues postulate that these TEMRA T cells are reflective of an accelerated aging of the immune system in PLWH despite effective viral suppression. Future studies from this research consortium will examine the interaction between these T cell subsets, CMV serostatus, age, and other information that has been collected over the duration of the Veterans Aging Cohort Study.
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