Integrating resident memory into T cell differentiation models

Abstract

Advances in the field of T cell memory, including the discovery of tissue residency, continue to add to the list of defined T cell subsets. Here, we briefly review the role of resident memory T cells (T_RM) in protective immunity, and propose that they exhibit developmental and migrational plasticity. We discuss T cell classification, the concept of cell type versus 'subset', and the difficulty of inferring developmental relationships between cells occupying malleable differentiation states. We propose that popular subsetting strategies do not perfectly define boundaries of developmental potential. We integrate T_RM into a 'terrace' model that classifies memory T cells along a continuous axis of decreasing developmental potential. This model also segregates cells on the basis of migration properties, although different migration properties are viewed as parallel differentiation states that may be permissive to change.

Figure 1.. The anatomic topology of primary and recall T cell responses.

A) During a primary infection, antigen drains from peripheral tissues to draining lymph nodes (LN) which activates naïve T cells specific for that pathogen. Cells expand in lymphoid tissue and migrate out to peripheral tissues to control the infection (which could be referred to as an inside-out immune response). B) At steady-state, memory T cells patrol for reinfection and are heterogeneous, consisting of resident cells that are absent from circulation (T_RM), cells that circulate through blood and lymph, and cells that recirculate though tissue using blood and lymph as conduits. C) Following secondary exposure to antigen, T_RM can proliferate, give rise to an expanded local population of long-lived progeny, redistribute to draining LNs where they may remain resident, and possibly rejoin the circulation. T_RM redistribution from the periphery to LNs and the circulating pool could be referred to as an outside-in immune response. Not pictured: Reactivation of LN circulating memory T cells (i.e., T_CM) recapitulates an inside-out immune response. D) Upon sensing cognate antigen within tissue, T_RM reactivate and alert the local immune system of a reinfection through chemokine and cytokine production. This leads to upregulation of interferon stimulated genes (ISGs), maturation of DCs, activation of T cells and NK cells, adhesion molecule upregulation and recruitment of CD8+ T cells and B cells. T_RM also proliferate and upregulate cytotoxic molecules, likely contributing to killing of infected cells.

Figure 2.. Memory T cell lineage.

Memory T cells are a product of a series of lineage specification events that define cell type. These commitments become fixed under physiologic conditions and cells are unable to transdifferentiate or dedifferentiate (e.g. B cells do not become T cells). We argue that memory T cell subsets should not be viewed as a few discrete and distinct cell types that occupy clear steps in a linear differentiation path, but rather comprise a heterogeneous constellation of cells. Hematopoietic stem cell (HSC); Common myeloid progenitor (CMP); Common lymphoid progenitor (CL); Lymph node (LN).

Figure 3.. Models of T cell differentiation.

A) Defined subsets of memory T cells imply unidirectional differentiation between discrete cell types. B) Initial modeling of electron dynamics implied discrete orbits of movement (left), whereas the modern view highlights a probabilistic distribution, represented as an electron cloud (right). C) The ‘terrace’ model depicts naïve cell activation (1) and differentiation into memory T cells (2) along a continuum of developmental potential (depicted as terraces), though most activated T cells (depicted in the river) die (3). Migration status is used to further bifurcate memory T cells into a resident and circulating pool. This migration status is largely fixed, though may not be permanent for all cells (4). Subset nomenclature of circulating memory T cells is estimated, but does not reflect discrete cell types with stepwise loss of differentiation potential (5). The ‘terrace’ model is based on developmental potential and migration properties. Stem cell memory T cells (T_SCM); Central memory T cells (T_CM); Effector memory T cells (T_EM); Exhausted T cell (T_EX).