Effect of age and sex on immune checkpoint expression and kinetics in human T cells

Abstract

Background Immune checkpoints are crucial molecules in maintaining a proper immune balance. Even though age and sex are known to have effects on the immune system, the interplay between age, sex and immune checkpoint expression by T cells is not known. The aim of this study was to determine whether age and sex affect immune checkpoint expression by T cells and if age and sex affect the kinetics of immune checkpoint expression following ex vivo stimulation. In this study, whole blood samples of 20 healthy young adults (YA, 9 males and 11 females) and 20 healthy older adults (OA, 9 males and 11 females) were stained for lymphocyte lineage markers and immune checkpoints and frequencies of CD28+, PD-1+, VISTA+ and CD40L+ T cells were determined. Immune checkpoint expression kinetics were studied following ex vivo anti-CD3/anti-CD28 stimulation of T cells from young and older healthy adults. Results We report an age-associated increase of CD40L + CD4+ and CD40L + CD8+ T-cell frequencies, whereas CD40+ B-cell frequencies were decreased in older adults, suggesting modulation of the CD40L-CD40 interaction with age. Immune checkpoint expression kinetics revealed differences in magnitude between CD4+ and CD8+ T cells independent of age and sex. Further analysis of CD4+ T-cell subsets revealed an age-associated decrease of especially PD-1 + CD4+ memory T cells which tracked with the female sex. Conclusion Collectively, our results demonstrate that both age and sex modulate expression of immune checkpoints by human T cells. These findings may have implications for optimising vaccination and immune checkpoint immunotherapy and move the field towards precision medicine in the management of older patient groups.

Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults

“…Notably, in this current study, we did not observe differences in expression of CTLA-4 or PD-1 between younger and older memory PB CD4 T cells (albeit from unmatched donor blood samples), potentially highlighting a gut-specific effect. Although previous studies have noted an age-associated increase in CTLA-4 or PD-1 expression on blood CD4 T cells [ 26 – 29 ], the lack of an apparent age effect observed here is in agreement with a number of other studies [ 30 – 33 ] and may relate to study populations (e.g. age range, sex) and/or the type of CD4 T cell evaluated (e.g.…”

“…A larger, well-controlled clinical study that includes participant-matched colonic tissue and blood samples and comprehensive clinical information is required to fully confirm our tissue-specific and age-related findings. Furthermore, given the recent observation of an age-associated decline of PD-1-expressing human PB CD4 T cells in specific memory subsets of older females [ 29 ], it will be important to determine if age and sex intersect to differentially impact phenotype and function of LP CD4 and CD8 T cells.…”

Dynamics and epigenetic signature of regulatory T-cells following antiretroviral therapy initiation in acute HIV infection

“…Males and persons of older age are known to have higher Tregs frequencies compared to females [119] , [120] , [121] and younger individuals [122] , [123] , [124] . Additionally, sex and age-related differences exist in the expression of immune checkpoints PD1 and CTLA4 [ 125 , 126 ], and, TGF-β1 [127] , [128] , [129] , [130] . In our study, we mainly included male individuals since the majority of participants in the Montreal primary infection (acute) cohort are male.…”

Immune checkpoint expression and relationships to anti‐PD‐L1 immune checkpoint blockade cancer immunotherapy efficacy in aged versus young mice

“… 41 A recent report on IC expression differences between young and aged adults showed that naïve CD4 + T cells in aged adults have higher expression of PD-1 versus young adults. 68 There is no data on PD-L1, PD-L2, or CD80 expression in elderly humans, to our knowledge.…”