Tissue-resident memory-like ILCs: innate counterparts of TRM cells

Abstract

Innate lymphoid cells (ILCs) are defined as lymphocytes that lack RAG recombinase and do not express diverse antigen receptors; however, recent studies have revealed the adaptive features of ILCs. Mouse cytomegalovirus (MCMV)- and cytokine-induced memory natural killer (NK) cells circulate in the blood and are referred to as conventional memory NK cells. In contrast, virus- and hapten-induced memory NK cells, hapten-induced memory ILC1s, and cytokine-induced memory-like ILC2s exhibit long-term residency in the liver or lung, and are referred to as tissue-resident memory ILCs. Considering their similar migration patterns and memory potential, tissue-resident memory ILCs could be regarded as innate counterparts of resident memory T (T_RM) cells. Both tissue-resident memory ILCs and T_RM cells share common characteristics in terms of dynamics, phenotype, and molecular regulation. The emergence of ILC memory expands the basic biology of ILCs and prompts us to re-examine their functions in disease progression. This review discusses the evidence supporting tissue-resident memory NK cells and other memory ILC subsets, compares them with T_RM cells, and highlights key unsolved questions in this emerging field.

Keywords: TRM cells; immunological memory; innate lymphoid cells; tissue-residency.

Figure 1

Memory formation and long-term maintenance of tissue-resident memory ILCs and conventional memory NK cells. Memory ILCs comprise MCMV- or IL-12/15/18-induced circulating populations, and hapten-, virus-, or IL-33-induced tissue-resident subsets. Antigen-specific cNK cells respond to MCMV via three signals, including recognition receptor Ly49H, co-stimulatory molecule DNAM-1, and pro-inflammatory cytokines. Effector Ly49H⁺ NK cells go through the expansion phase under the control of transcription factors, such as Zbtb32, STAT1/4, Runx1/3, and CBF-β. A small fraction of effector Ly49H⁺ NK cells can survive against apoptosis to generate a memory pool. Memory Ly49H⁺ NK cells circulate in the blood and populate throughout the body. Cytokine-induced non-specific memory cNK cells also show similar migration patterns. Apart from these circulating memory NK cells, hapten-induced memory NK cells and ILC1s exhibit long-term residency in the liver. CD49b⁺ cNK cells may recognize haptens or hapten-peptide complexes dependently on the Ly49C/I receptors. Inflammatory cytokines IFN-α/β and IL-12 drive the memory formation of hapten-specific liver NK cells. Of note, key factors contributing to the retention of memory CD49b⁺ cNK cells have not been determined. CD49a⁺CXCR6⁺ NK cells can mediate recall responses to different viruses and haptens; however, the associated recognition receptors remain largely unknown. Both CD49b⁺Ly49C/I⁺ and CD49a⁺CXCR6⁺ NK cells prefer to reside in the liver after memory formation. Haptens also induce memory IL-7Rα⁺ ILC1 generation in draining LNs. The LN-derived memory ILC1s selectively maintain their longevity in the liver via CXCR6 and IL-7. In addition, IL-33-experienced lung ILC2s exhibit higher responsiveness to IL-33 and IL-25, confirming their memory-like features