Pre-existing T Cell Memory to Novel Pathogens

Abstract

Immunological experiences lead to the development of specific T and B cell memory, which readies the host for a later pathogen rechallenge. Currently, immunological memory is best understood as a linear process whereby memory responses are generated by and directed against the same pathogen. However, numerous studies have identified memory cells that target pathogens in unexposed individuals. How "pre-existing memory" forms and impacts the outcome of infection remains unclear. In this review, we discuss differences in the composition of baseline T cell repertoire in mice and humans, factors that influence pre-existing immune states, and recent literature on their functional significance. We summarize current knowledge on the roles of pre-existing T cells in homeostasis and perturbation and their impacts on health and disease.

FIGURE 1.

The baseline T cell repertoire dynamically evolves over time. The T cell repertoire is shaped by a combination of endogenous immune processes and external inputs from the environment. In young children, it consists mainly of diverse naive T cells with robust proliferative and differentiation potential. T cell stimulation from cognate Ags, cross-reactive epitopes, cytokine signals, and other changes in the cellular environment influence T cell differentiation and the establishment of immunological memory. Memory T cells exhibit rapid, specialized responses, express diverse trafficking receptors, and provide surveillance in circulation and tissue environments.

FIGURE 2.

The pre-existing memory repertoire is composed of a diverse array of T cells. (A) Flexible TCR recognition enables T cell memory elicited by a particular Ag to recognize and respond to a range of other peptide–MHC complexes. For example, pre-existing memory to SARS-CoV-2 includes cross-reactive T cells that recognize Ags from HCoV, commensal microbes, and likely other yet-to-be-defined sources. (B) The pre-existing repertoire includes memory phenotype T cells that have already acquired disparate differentiation states. (C) Memory precursors express tissue-homing receptors. Different tissue tropism is likely imprinted by prior Ag encounters and reveals unique histories of antigenic experiences. (D) The memory repertoire established from past exposures consists of a diverse population of T cells with varying levels of TCR binding strength and responsiveness to cross-reactive Ags.

FIGURE 3.

Divergent influences of pre-existing T cell memory. Pre-existing functional polarization may contribute to varied responses after stimulation. Having an existing reservoir of TRMs or the ability to rapidly mobilize tissue surveillance may facilitate local immunity but could also lead to immunopathology if inappropriately regulated. The impact of pre-existing memory T cells is likely context dependent and can have both positive and negative influences on immune health. Future strategies aimed at selectively modulating pre-existing memory may provide new opportunities to enhance protective immunity against cancer or infection and restore immune tolerance in autoimmune diseases.