Functional classification of memory CD8+ T cells by CX3CR1 expression

Abstract

Localization of memory CD8+ T cells to lymphoid or peripheral tissues is believed to correlate with proliferative capacity or effector function. Here we demonstrate that the fractalkine-receptor/CX3CR1 distinguishes memory CD8+ T cells with cytotoxic effector function from those with proliferative capacity, independent of tissue-homing properties. CX3CR1-based transcriptome and proteome-profiling defines a core signature of memory CD8+ T cells with effector function. We find CD62LhiCX3CR1+ memory T cells that reside within lymph nodes. This population shows distinct migration patterns and positioning in proximity to pathogen entry sites. Virus-specific CX3CR1+ memory CD8+ T cells are scarce during chronic infection in humans and mice but increase when infection is controlled spontaneously or by therapeutic intervention. This CX3CR1-based functional classification will help to resolve the principles of protective CD8+ T-cell memory.

The (gradual) rise of memory inflation

“…CX3CR1 binds fractalkine, a chemokine important in tissue homing. It has recently been shown that CD8 + T cells expressing high surface levels of CX3CR1 lack proliferative capacity and have been described as “terminally differentiated” 60. To that extent, this fits with many descriptions of CD8 T‐cell phenotypes associated with CMV in mouse and man.…”

“…To that extent, this fits with many descriptions of CD8 T‐cell phenotypes associated with CMV in mouse and man. Additionally, there exist subpopulations of cells that express intermediate levels of CX3CR1 60. These are of particular interest in the setting of inflation as they possess both an “effector‐memory” phenotype typical of sustained antigen re‐encounter, but also proliferative capacity.…”

“…The functions in vivo are not yet well explored but it might be they perform some similar “tuning” activity eg, in preventing overstimulation and promoting long‐term survival. Expression of KLRG1—which has well‐documented inhibitory functions—is often used as a marker for this type of cell population 60, 62. In contrast, NKG2D is stimulatory, so the balance between signaling through such receptors may be critical for activation as it is in NK cells.…”

“…There are 2 likely explanations for this—one is that these proliferating cells are derived from a central memory pool which can expand, differentiate, and redistribute to organs very rapidly 50. The other is that an “intermediate” pool of cells exist (as described for the CX3CR1‐intermediate pool) which possesses features of differentiation but retains proliferative capacity 60. Since these “intermediate” cells may be found in organs, this would allow for some local expansion in situ if antigen is presented 67…”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…CD8 + CD57 + T cell frequencies are especially increased in the elderly, they have strong cytotoxic potential, high expression of adhesion molecules, strong migratory potential toward nonlymphoid organs and – indicative of a cytotoxic effector memory phenotype – they depict expression of CX3CR1. It is believed that CD8 + CD57 + T cells are highly differentiated antigen‐driven effector cells in a state of replicative senescence with limited capacities to proliferate 88, 89, 90, 91, 92. Recent reports, however, suggest that these CD8 + CD57 + CD28 − T cells might comprise a rather heterogeneous group of highly antigen‐experienced cells that, depending on the immunobiological context and stimuli, differ in their susceptibility to apoptosis and their capability to proliferate and expand 84, 93, 94, 95…”