Hidden memories: frontline memory T cells and early pathogen interception

Abstract

Immunologic memory reflects the ability of a host to more effectively respond to a re-encounter with a particular pathogen than the first encounter, and when a vaccine mimics the first encounter, comprises the basis of vaccine efficacy. For T cells, memory is often equated with the anamnestic response, the ability of secondary lymphoid tissue-based (central) memory T cells to respond to pathogen exposure with a more rapid and higher magnitude production and infection-site delivery of pathogen-specific effector cells than observed in naive hosts. However, increasing evidence supports a fundamentally different kind of T cell memory in which differentiated, long-lived effector memory T cells, prepositioned in sites of potential pathogen invasion or rapidly mobilized to such sites from blood and marginated pools, intercept and potentially control/eliminate pathogen within hours of infection. In this article, we review the evidence for this "hidden" T cell memory and its implication for vaccine development.

Figure 1. Contribution of each memory T cell subset varies at each phase of response and is mandated by anatomic location and functional specialization

In the uninfected host, resident (rT_EM) and migrating (mT_EM) effector memory T cells are the only subsets present within non-lymphoid effector sites, which represent the most common sites of initial pathogen exposure. Immediately upon infection, the density of local memory T cells is critical and proliferation potential is irrelevant. rT_EM and mT_EM present at the point of entry are the only subsets that participate in protection at this time. Early (<3–4 days) after infection, recruitment to sites of inflammation is critical and proliferation potential is still irrelevant. The presence of recruitable T_EM cell populations from blood (bT_EM) may substantially increase the local effector to infected target ratio. If a secondary infection is not contained rapidly at the portal of entry by T_EM subsets (e.g., a reproductive ratio - R0 - of infection of > 1), T_CM undergo re-activation in draining lymph nodes (or other SLTs), which results in extensive proliferation, differentiation and production of an abundant new wave of effectors, which migrate to the sites of infection. This phase of the response occurs late (≥4 days), and is particularly important when T_EM densities in tissues are too low to contain infection.