Age-associated increase in lifespan of naïve CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects

Abstract

With age, T-cell generation from the thymus is much reduced, yet a substantial naïve T-cell pool is maintained even in aged animals, suggesting that naïve T cells either persist longer or turn over faster to maintain T-cell homeostasis. We found that with age, naïve CD4 T cells became progressively longer-lived. Their longer lifespan did not depend on recognition of self-peptide/class II. Newly generated naïve T cells derived from aged stem cells had a shorter lifespan, like that of young naïve T cells. Conversely, naïve CD4 T cells derived from middle-aged thymectomized mice were longer-lived in vivo, and their development of functional defects was accelerated. These observations suggest that naïve T cells develop their longer lifespan during their sojourn in the periphery. Increased longevity of naïve CD4 T cells correlated well with reduced expression of proapoptotic molecule Bim. We suggest that the intrinsic increase in longevity helps maintain naïve T-cell homeostasis but facilitates the development of functional defects in mice.aging ͉ Bim ͉ T lymphocytes ͉ apoptosis A ging is accompanied by pleiotropic changes in the immune system that lead to dysfunction of cellular and humoral immune responses (1, 2). The progressive decline in functions is associated with increased susceptibilities to infectious disease, autoimmune disease, and cancer (3-5). Naïve CD4 T cells from aged animals exhibit age-related decreases in Ag responsiveness, characterized by weak proliferative response, lower IL-2 production, and a poor ability to help B cells, leading to reduced specific antibody production (6-8). Similar functional defects are observed when aged naïve CD4 T cells are transferred to young hosts (9, 10), indicating that many of the aged-related defects are intrinsic to the naïve CD4 T cells.When depletion of naïve CD4 T cells with an endogenous superantigen (11), by anti-CD4 Ab given systemically, or by lethal irradiation followed by aged bone marrow (BM) reconstitution, leads to reconstitution of naïve T cells in aged mice, the newly generated CD4 T cells function much like cells from young mice, even though they are derived from aged stem cells (10,12,13). This suggests age-associated loss of function occurs primarily while naïve CD4 T cells persist in periphery. However, no particular mechanism(s) leading to such dysfunction has been identified.The size of the naïve T-cell population is determined by the rate of emigration of new naïve T cells from thymus and by homeostatic turnover of T cells in the periphery. T-cell homeostasis has been assumed to be achieved largely by T-cell receptor (TCR) engagement with self-peptide/MHC (14, 15) and homeostatic survival factors, such as 17). Another important component is cellular lifespan, which has often been considered a cell-intrinsic property. The homeostatic equilibriums that regulate the size of the naïve T-cell pool in aged animals may differ from those in young. Thymic involution starts at puberty and causes an abrupt decline of at least 10-fold in new thymic emig...

Myeloid-Derived Suppressor Cells Attenuate TH1 Development through IL-6 Production to Promote Tumor Progression

“…For intracellular staining, following isolation of effector CD4 þ T cells from the in vitro cultures or from mice using anti-CD4 beads, CD4 þ T cells were stimulated with cognate peptide-pulsed dendritic cell or phorbol 12-myristate 13-acetate (PMA)/ionomycin in vitro and were stained with Alexa Flour 488-anti-IFN-g, PE-anti-IL-2 or -anti-IL-17A antibody (eBioscience; ref. 34). For the analysis of IL-6 production in MDSC, splenocytes harvested from tumor-free or -bearing mice were cultured with Brefeldin A (Sigma) in vitro, and 12 hours later, cells were analyzed for intracellular IL-6.…”

Interleukin‐21 administration to aged mice rejuvenates their peripheral T‐cell pool by triggering de novo thymopoiesis

“…Thymic involution cannot solely account for impaired immune responses as additional T‐cell intrinsic defects appear in ageing naïve T cells due to prolonged post‐thymic lifespan (Haynes & Swain, 2006; Maue et al ., 2009; Tsukamoto et al ., 2009). More specifically, TCR activation is blunted with ageing due to increased cytoplasmic concentration of phosphatases known for inhibiting TCR signaling (Li et al ., 2012).…”

“…Repeated observations revealed that beside scarcity of T‐cell precursors in the pre‐immune repertoire, IL‐2 production, cell surface expression of CD25, and T‐cell proliferation are all greatly reduced in ageing hosts (Haynes & Swain, 2006; Maue et al ., 2009; Tsukamoto et al ., 2009). Elevated secretion levels of pro‐inflammatory cytokines such as interferon (IFN)γ caused by the accumulation of CD44 hi T cells were also reported to play a role in accelerating age‐related immunosenescence (Zhang et al ., 2002; Decman et al ., 2012).…”

“…Although some aspects of age‐related decline in T‐cell responses reflect systemic changes, others are due to cell intrinsic defects (Haynes & Swain, 2006; Maue et al ., 2009; Tsukamoto et al ., 2009). We show in this report that administration of rIL‐21 enhances thymopoiesis in aged mice through expansion of both the stromal and responsive thymocytes compartments without the induction of any apparent pathology in peripheral organs.…”

“…The net outcome culminates in TCR repertoire skewing with a noticeable increase in the number of effector/memory T cells (Zanni et al ., 2003). Notably, a growing body of literature established that while the size of the peripheral T‐cell compartment remains unchanged throughout ageing, an increase in post‐thymic lifespan of T cells takes place consequently leading to the emergence of T‐cell intrinsic defects (Haynes & Swain, 2006; Maue et al ., 2009; Tsukamoto et al ., 2009). For instance, naïve CD4 + T cells derived from aged mice display defects in TCR threshold calibration, do not readily form immunological synapses, and have a marked reduction in the recruitment of TCR‐associated signaling molecules when compared to younger mice (Garcia & Miller, 1997, 2001, 2002; Tamir et al ., 2000).…”