Abstract
Immunosenescence is a progressive deterioration of the immune system with aging. It affects both innate and adaptive immunity limiting the response to pathogens and to vaccines. As chronic cytomegalovirus (CMV) infection is probably one of the major driving forces of immunosenescence, and its persistent infection results in functional and phenotypic changes to the T-cell repertoire, the aim of this study was to analyze the effect of CMV-seropositivity and aging on the expression of CD300a and CD161 inhibitory receptors, along with the expression of CD57 marker on CD4+, CD8+, CD8+CD56+ (NKT-Like) and CD4−CD8− (DN) T-cell subsets. Our results showed that, regardless of the T-cell subset, CD57−CD161−CD300a+ T-cells expand with age in CMV-seropositive individuals, whereas CD57−CD161+CD300a+ T-cells decrease. Similarly, CD57+CD161−CD300a+ T-cells expand with age in CMV-seropositive individuals in all subsets except in DN cells and CD57−CD161+CD300a− T-cells decrease in all T-cell subsets except in CD4+ T-cells. Besides, in young individuals, CMV latent infection associates with the expansion of CD57+CD161−CD300a+CD4+, CD57−CD161−CD300a+CD4+, CD57+CD161−CD300a+CD8+, CD57−CD161−CD300a+CD8+, CD57+CD161−CD300a+NKT-like, and CD57+CD161−CD300a+DN T-cells. Moreover, in young individuals, CD161 expression on T-cells is not affected by CMV infection. Changes of CD161 expression were only associated with age in the context of CMV latent infection. Besides, CD300a+CD57+CD161+ and CD300a−CD57+CD161+ phenotypes were not found in any of the T-cell subsets studied except in the DN subpopulation, indicating that in the majority of T-cells, CD161 and CD57 do not co-express. Thus, our results show that CMV latent infection impact on the immune system depends on the age of the individual, highlighting the importance of including CMV serology in any study regarding immunosenescence.
Highlights
The human CD300 family has seven members, including the inhibitory receptor CD300a, which has been proposed as a possible biomarker for diagnosis and therapeutic target in several pathological situations [1,2,3,4]
Here, we study the effect of CMV latent infection and age on the expression of CD161 and CD300a receptors on CD4+, CD8+, CD8+CD56+ (NKT-like), and CD4−CD8− (DN) T-cell subsets and their relation with the polyfunctionality marker CD57, which is a hallmark of CMV infection and aging in T-cells [37, 38]
Multicolor flow cytometry was used to analyze the expression of CD57, CD161, and CD300a markers on CD4+, CD8+, NKT-like, and DN T-cell subpopulations from healthy individuals stratified by age and CMV-serostatus (Table 1)
Summary
The human CD300 family has seven members, including the inhibitory receptor CD300a, which has been proposed as a possible biomarker for diagnosis and therapeutic target in several pathological situations (i.e., infectious diseases and cancer) [1,2,3,4]. Human CD300a receptor is expressed on the surface of T [5, 6] and natural killer (NK) cells [7, 8]. On CD8+ T-cells, CD300a expression has been shown to associate with better cytotoxic function [10] and CD300a+CD4+ T-cells are associated with polyfunctionality and, upon stimulation, upregulate the transcription factor Eomesodermin (Eomes) [6, 11]. It has been shown that CD161 expression on T-cells characterizes a transcriptional and functional T-cell phenotype that is TCR- and cell lineage-independent [17]. CD161 has been shown to function as a costimulatory receptor in the context of TCR stimulation [18, 19]. While the role of CD161 receptor on NK cells is agreed to be inhibitory [12, 20, 21], on T-cells, there is lack of consensus, as there is evidence of both costimulatory [20, 22] and inhibitory [18, 19] effects
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