Signaling pathways in aged T cells – A reflection of T cell differentiation, cell senescence and host environment

With increasing age, the ability of the immune system to protect against new antigenic challenges or to control chronic infections erodes. Decline in thymic function and cumulating antigenic experiences of acute and chronic infections threaten T cell homeostasis, but insufficiently explain the failing immune competence and the increased susceptibility for autoimmunity. Alterations in signaling pathways in the aging T cells account for many of the age-related defects. Signaling threshold calibrations seen with aging frequently built on mechanisms that are operational in T cell development and T cell differentiation or are adaptations to the changing environment in the aging host. Age-related changes in transcription of receptors and signaling molecules shift the balance towards inhibitory pathways, most dominantly seen in CD8 T cells and to a lesser degree in CD4 T cells. Prominent examples are the expression of negative regulatory receptors of the CD28 and the TNF receptor superfamilies as well the expression of various cytoplasmic and nuclear dual-specific phosphatases.

► Mechanisms of TCR threshold calibration in T cell differentiation and aging are shared.
► The cytokine milieu in the aging host attenuates signaling cascades.
► The aging T cell is biased towards negative regulatory pathways.
► Negative regulatory receptors (ILT2, KIRs and KLRG1) interfere with pro-proliferative signals.
► Increased expression of dual-specific phosphatases attenuates MAP kinase pathways.