Coordinated Regulation of NK Receptor Expression in the Maturing Human Immune System

Abstract

Natural killer (NK) cells are responsible for recognizing and killing transformed, stressed, and infected cells. They recognize a set of non-antigen-specific features termed “altered self” through combinatorial signals from activating and inhibitory receptors. These natural killer cell receptors (NKR) are also expressed on CD4+ and CD8+ T cells, B cells, and monocytes, though a comprehensive inventory of NKR expression patterns across leukocyte lineages has never been performed. Using mass cytometry, we found that NKR expression patterns distinguish cell lineages in human peripheral blood. In individuals with high levels of CD57, indicative of a mature immune repertoire, NKR are more likely to be expressed on non-NK cells, especially CD8+ T cells. Mature NK and CD8+ T cell populations show increased diversity of NKR surface expression patterns, but with distinct determinants: mature NK cells acquire primarily inhibitory receptors, while CD8+ T cells attain a specific subset of both activating and inhibitory receptors, potentially imbuing them with a distinct functional role. Concurrently, monocytes show decreased expression of the generalized inhibitory receptor LILRB1, consistent with an increased activation threshold. Therefore, NKR expression is coordinately regulated as the immune system matures, resulting in the transfer of “altered self” recognition potential among leukocyte lineages. This likely reduces antigen specificity in the mature human immune system, and implies that vaccines and therapeutics that engage both its innate and adaptive branches may be more effective in the settings of aging and chronic infection.

Convergence of Innate and Adaptive Immunity during Human Aging

“…The frequency of NKR-expressing T cells not only increases with age but also in conditions associated with chronic immune activation (66–68). Among the most commonly observed NKR on T cells are activating and inhibitory receptors, such as CD16, CD56, CD57, NKp30, KLRG1, and CD94, members of the NK receptor G2 (NKG2), and killer-cell immunoglobulin-like receptor (KIR) families (10, 66–69). …”

“…NK and T lymphocytes have a common origin from a lymphoid progenitor cell in the bone marrow (9), and recent comparative proteomic and transcriptomic studies have demonstrated a remarkably close proximity between effector αβCD8 + T lymphocytes and NK cells (10, 11), reiterating an evolutionary ancestry and shared biology between the two cell lineages.…”

The Broad Spectrum of Human Natural Killer Cell Diversity

“…adaptive) immunity is complemented by a much more rapid innate response in part mediated by NK cells (Deguine and Bousso, 2013; Jain and Pasare, 2017). However, this is an overly simplified view of T cell and NK cell responses and functions, because T cells can express many NK cell-associated receptors including MHC class I-binding receptors (Davis et al, 2015; Strauss-Albee et al, 2014). In addition, NK cells can adapt through epigenetic remodeling in response to environmental exposures and can even form long-lasting immunological memory (O’Sullivan et al, 2015; Tesi et al, 2016).…”

Natural killer cell heterogeneity: cellular dysfunction and significance in HIV-1 immuno-pathogenesis

“…For example, the uterine, mucosal and liver-resident NK cells phenotypically differ from their blood counterpart [8]. Peripheral blood NK cell diversity is highly complex; recent studies have described more than a thousand phenotypes [9] sharing NK cell receptors (NKRs), across the leucocyte lineages [10]. However, their significance in human pathophysiology is elusive.…”