Peripheral residence of naïve CD4 T cells induces MHC class II-dependent alterations in phenotype and function

Abstract

BackgroundAs individual naïve CD4 T lymphocytes circulate in the body after emerging from the thymus, they are likely to have individually varying microenvironmental interactions even in the absence of stimulation via specific target recognition. It is not clear if these interactions result in alterations in their activation, survival and effector programming. Naïve CD4 T cells show unimodal distribution for many phenotypic properties, suggesting that the variation is caused by intrinsic stochasticity, although underlying variation due to subsets created by different histories of microenvironmental interactions remains possible. To explore this possibility, we began examining the phenotype and functionality of naïve CD4 T cells differing in a basic unimodally distributed property, the CD4 levels, as well as the causal origin of these differences.ResultsWe examined separated CD4hi and CD4lo subsets of mouse naïve CD4 cells. CD4lo cells were smaller with higher CD5 levels and lower levels of the dual-specific phosphatase (DUSP)6-suppressing micro-RNA miR181a, and responded poorly with more Th2-skewed outcomes. Human naïve CD4lo and CD4hi cells showed similar differences. Naïve CD4lo and CD4hi subsets of thymic single-positive CD4 T cells did not show differences whereas peripheral naïve CD4lo and CD4hi subsets of T cell receptor (TCR)-transgenic T cells did. Adoptive transfer-mediated parking of naïve CD4 cells in vivo lowered CD4 levels, increased CD5 and reactive oxygen species (ROS) levels and induced hyporesponsiveness in them, dependent, at least in part, on availability of major histocompatibility complex class II (MHCII) molecules. ROS scavenging or DUSP inhibition ameliorated hyporesponsiveness. Naïve CD4 cells from aged mice showed lower CD4 levels and cell sizes, higher CD5 levels, and hyporesponsiveness and Th2-skewing reversed by DUSP inhibition.ConclusionsOur data show that, underlying a unimodally distributed property, the CD4 level, there are subsets of naïve CD4 cells that vary in the time spent in the periphery receiving MHCII-mediated signals and show resultant alteration of phenotype and functionality via ROS and DUSP activity. Our findings also suggest the feasibility of potential pharmacological interventions for improved CD4 T cell responses during vaccination of older people via either anti-oxidant or DUSP inhibitor small molecules.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-014-0106-0) contains supplementary material, which is available to authorized users.

Correlation of cell‐surface CD8 levels with function, phenotype and transcriptome of naive CD8 T cells

“…We have previously reported functional heterogeneity in naive CD4 T cells associated with subtly differing CD4 levels . We therefore began to examine if naive CD8 T cells showed similar heterogeneity.…”

“…Venous blood was collected from healthy, young, adult volunteers (aged 22–35 years with equal representation of men and women) after obtaining written consent. Peripheral blood mononuclear cells were separated from heparinized blood by density‐gradient centrifugation as described previously . The procedures followed were approved by the Institutional Human Ethics Committee of the National Institute of Immunology.…”

“…In this context, we have previously reported that naive CD4 T cells in aged mice show heterogeneity of hypo‐responsiveness, suggesting that the population consists of cohorts with differing functionalities, and that cellular post‐thymic aging, via MHC class II (MHCII) ‐mediated signals, may contribute to the generation of this heterogeneity of responsiveness . However, there is evidence that homeostatic maintenance pathways, including but not limited to the role of MHC‐mediated ‘tonic’ signals regulating the survival of naive post‐thymic T cells in the periphery, may be somewhat different for CD4 versus CD8 T cells, making it interesting to examine potential co‐receptor‐associated functional heterogeneity in naive CD8 T cells.…”

Roles of Reactive Oxygen Species in Rheumatoid Arthritis Pathogenesis

“…Naïve T cells in old people have more chance to accumulate genomic DNA damage than those in young people because these cells in older people have a relatively long life span in the periphery and are exposed to oxidative stress [28]. DNA damage such as DNA double-strand breaks needs to be detected and repaired by DNA damage repair pathways in order to maintain genomic stability.…”

“…The increased expression of cytokines IL-1β, IL-6, and TNF-α play key roles in the initiation of arthritis and pathogenesis of destructive arthritis in experimental animal models [67]. As thymic activity decreases around the age of 40 to 50 years, prolonged residence of naïve T cells in the periphery progressively lead to the accumulation of oxidative DNA damage [28]. A defect in the maintenance of genomic integrity with age causes excessive loss of peripheral T cells that needs to be compensated by homeostatic proliferation to maintain compartment size and leads to the eventual emergence of senescence biomarkers.…”