T Cells Going Innate

Abstract

Natural killer (NK) cell receptors (NKRs) play a crucial role in the homeostasis of antigen-experienced T cells. Indeed, prolonged antigen stimulation may induce changes in the receptor repertoire of T cells to a profile that features NKRs. Chronic antigen exposure, at the same time, has been shown to trigger the loss of costimulatory CD28 molecules with recently reported intensified antigen thresholds of antigen-experienced CD8(+) T cells. In transplantation, NKRs have been shown to assist allograft rejection in a CD28-independent fashion. We discuss here a role for CD28-negative T cells that have acquired the competency of the NKR machinery, potentially promoting allorecognition either through T cell receptor (TCR) crossreactivity or independently from TCR recognition. Collectively, NKRs can bring about innate-like T cells by providing alternative costimulatory pathways that gain relevance in chronic inflammation, potentially leading to resistance to CD28-targeting immunosuppressants.

Keywords: NK cell receptors; T cells; adaptive immunity; innate immunity; transplantation.

Figure 1. Key Figure: T cells acquire innate characteristics by expressing NK cell receptors subsequent to chronic antigen challenge

Antigen-presenting cells (APC) stimulate TCR/CD28-mediated signals and activation (blue). Antigen-experienced memory T cells may lose CD28 and require an augmented antigen threshold over time, thus supporting a resistance to classical adaptive stimulatory pathways (grey). Chronic antigen challenge, in turn, may induce the expression of NK cell receptors (NKRs) on some T cell clones (pink), ultimately facilitating the response of antigen-experienced T cells based on acquired NKR signaling . Those mechanisms may compensate for the lost capacity of conventional adaptive pathways (purple). APC , antigen-present ing cell; TCR , T cell receptor; Ag, antigen; sNKR, stimulatory NK cell receptor; iNKR, inhibiting NK cell receptor ; SL, stimulatory ligand; IL, inhibiting ligand.

Figure 2. Clonal development of innate-like T cells is impacted by chronic antigen exposure and cytokine environment

Subsequent to an initial antigen encounte r (yellow) facilitated by antigen-presenting cells (APCs), some na·ive T cells evolve into memory T cells (blue) . With chronic antigenic TCR stimulation and/or the presence of cytokines including IL-15 (red), specific T cell clones (light purple) within the pool of memory T cells may either develop characteristics of innate-like T cells (dark purple) or remain conventional memory T cells. Changes in the innate T cell potential are depicted by the purple colored shading of the vertical bar.