T-cell immunosenescence: lessons learned from mouse models of aging

Abstract

It is well established that increasing age is associated with a decreased capacity of the immune system to mediate effective immune responses to vaccination and invading pathogens. Because of the inherent limitations of conducting experiments in humans, much of what we have learned is owed to the utility of experimental mouse models of aging. Recent studies performed in the mouse have demonstrated mechanisms responsible for age-related declines in the function of CD4+ and CD8+ cells. This review describes key findings regarding age-related defects in T-cell function and discusses the impact these defects have on vaccine efficacy and immunity.

A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4+T cell receptor repertoire clonality

“…2 As humans age, immune responses become impaired, characterized by (1) reduced lymphopoiesis of new na€ ıve B and T cells, with novel BCRs 6 and TCRs, 7 respectively, (2) reduced dendritic cell (DC) function resulting in poor responses to inflammatory signals and lowered capacity to present antigen and to activate adaptive immune responses, 8 (3) poor germinal center formation, site of B cell expansion and selection, 9 and (4) decreased potential for T cell expansion, expression of activation markers, production of cytokines, diversity of TCR repertoire and delayed T cell responses to antigen. 7,10 Thus, these changes during aging help to explain the increased susceptibility to infection and reduced response to vaccinations in the elderly population. 3,11,12 Previous work has characterized the presence of immune cells organized as ectopic lymphoid structures, referred as tertiary lymphoid structures (TLS), in the tumor of non-small cell lung cancer (NSCLC) patients.…”

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).…”