Immunosenescence is a series of age-related changes that affect the immune system and, with time, lead to increased vulnerability to infectious diseases. This Review addresses recent developments in the understanding of age-related changes that affect key components of immunity, including the effect of aging on cells of the (mostly adaptive) immune system, on soluble molecules that guide the maintenance and function of the immune system and on lymphoid organs that coordinate both the maintenance of lymphocytes and the initiation of immune responses. I further address the effect of the metagenome and exposome as key modifiers of immune-system aging and discuss a conceptual framework in which age-related changes in immunity might also affect the basic rules by which the immune system operates.

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In the thymus, a diverse and polymorphic T-cell repertoire is generated by random recombination of discrete T-cell receptor (TCR)-alphabeta gene segments. This repertoire is then shaped by intrathymic selection events to generate a peripheral T-cell pool of self-MHC restricted, non-autoaggressive T cells. It has long been postulated that some optimal level of TCR diversity allows efficient protection against pathogens. This article focuses on several recent advances that address the required diversity for the generation of an optimal immune response.

We conducted a serological study to define correlates of immunity against SARS-CoV-2. Relative to mild COVID-19 cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against nucleocapsid (N) and the receptor binding domain (RBD) of spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months post-onset, whereas α-N titers diminished. Testing of 5882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.