Abstract
A hallmark of human immunosenescence is the accumulation of late-differentiated memory CD8+ T cells with features of replicative senescence, such as inability to proliferate, absence of CD28 expression, shortened telomeres, loss of telomerase activity, enhanced activation, and increased secretion of inflammatory cytokines. Importantly, oligoclonal expansions of these cells are associated with increased morbidity and mortality risk in elderly humans. Currently, most information on the adaptive immune system is derived from studies using peripheral blood, which contains approximately only 2% of total body lymphocytes. However, most lymphocytes reside in tissues. It is not clear how representative blood changes are of the total immune status. This is especially relevant with regard to the human gastrointestinal tract (GALT), a major reservoir of total body lymphocytes (approximately 60%) and an anatomical region of high antigenic exposure. To assess how peripheral blood T cells relate to those in other locations, we compare CD8+ T cells from peripheral blood and the GALT, specifically rectosigmoid colon, in young/middle age, healthy donors, focusing on phenotypic and functional alterations previously linked to senescence in peripheral blood. Overall, our results indicate that gut CD8+ T cells show profiles suggestive of greater differentiation and activation than those in peripheral blood. Specifically, compared to blood from the same individual, the gut contains significantly greater proportions of CD8+ T cells that are CD45RA- (memory), CD28-, CD45RA-CD28+ (early memory), CD45RA-CD28- (late memory), CD25-, HLA-DR+CD38+ (activated) and Ki-67+ (proliferating); ex vivo CD3+ telomerase activity levels are greater in the gut as well. However, gut CD8+ T cells may not necessarily be more senescent, since they expressed significantly lower levels of CD57 and PD-1 on CD45RO+ memory cells, and had in vitro proliferative dynamics similar to that of blood cells. Compartment-specific age-effects in this cohort were evident as well. Blood cells showed a significant increase with age in proportion of HLA-DR+38+, Ki-67+ and CD25+ CD8+ T cells; and an increase in total CD3+ ex-vivo telomerase activity that approached significance. By contrast, the only age-effect seen in the gut was a significant increase in CD45RA- (memory) and concurrent decrease in CD45RA+CD28+ (naïve) CD8+ T cells. Overall, these results indicate dynamics of peripheral blood immune senescence may not hold true in the gut mucosa, underscoring the importance for further study of this immunologically important tissue in evaluating the human immune system, especially in the context of chronic disease and aging.
Highlights
Immunosenescence, the age-associated decline in immune competence, is characterized by a wide range of functional and phenotypic alterations to the immune system [1, 2]
Our data show that in the CD8+ T cell compartment, the gut had a significantly higher proportion of CD45RA- and CD28- cells. Looking at these markers together, there was a lower proportion of CD4RA+CD28+ naïve, and higher proportion of CD45RA-CD28+ early memory and CD45RA-CD28- late memory CD8+ T cells. These results accord with earlier studies indicating that the gut CD8+ compartment is more differentiated than blood, presumably due to chronic antigenic stimulation [35]
The gut is a primary line of defense that routinely faces antigenic challenges, as opposed to the blood, which is primarily a conduit for trafficking lymphocytes
Summary
Immunosenescence, the age-associated decline in immune competence, is characterized by a wide range of functional and phenotypic alterations to the immune system [1, 2]. This constellation of features is associated with increased susceptibility to infectious diseases and cancer, reduced effectiveness of vaccination, increased autoimmune phenomena, tissue damage due todysregulated inflammation, and higher mortality risk [3,4,5,6]. An important caveat regarding research on human immunosenescence is that most studies have been performed on peripheral blood, which contains only 2% of total body lymphocytes. There is minimal information on the relationship of CD8+ T cells within the GALT and peripheral blood, and how the composite of these two populations contributes to immunosenescence
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