Memory formation and long-term maintenance of IL-7Rα+ ILC1s via a lymph node-liver axis

Abstract

Natural killer (NK) cells are reported to have immunological memory, with CD49a+ liver-resident NK cells shown to confer hapten-specific memory responses, but how this memory is induced or maintained is unclear. Here we show that memory type I innate lymphoid cells (ILC1s), which express IL-7Rα, are generated in the lymph nodes (LNs) and require IL-7R signaling to maintain their longevity in the liver. Hapten sensitization initiates CXCR3-dependent recruitment of IL-7Rα+ ILC1s into skin-draining LNs, where they are primed and acquire hapten-specific memory potential. Memory IL-7Rα+ ILC1s then exit draining LNs and are preferentially recruited, via CXCR6, to reside in the liver. Moreover, long-term blockade of IL-7R signaling significantly reduces ILC1-mediated memory responses. Thus, our results identify a memory IL-7Rα+ ILC1 population and reveal a LN-liver axis that is essential for ILC1 memory generation and long-term maintenance.

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

“…Liver-resident NK cells develop dependently on the transcription factors T-bet and Hobit (Sojka et al, 2014;Mackay et al, 2016), in contrast to Eomes-dependent conventional NK (cNK) cells (Sojka et al, 2014); thus, they represent a distinct lineage from bone marrow-derived cNK cells. More interestingly, CD49a + liver-resident NK cells highly express CXCR6, whereas CD49b + cNK cells lack the expression of CXCR6 (Peng et al, 2013a;Wang et al, 2018). After skin sensitization with the hapten fluorescein isothiocyanate (FITC), a few FITC-positive cells can be found in the liver (Peng et al, 2013a).…”

“…In addition, molecules associated with homing and activation, such as CXCR6, CD62L, CD18, and NKG2D, play a role in liver NK cell-mediated memory responses (O'Leary et al, 2006). Among these surface molecules, Ly49C/I and CD62L are expressed on CD49b + cNK cells at much higher levels than on liver-resident NK cells at steady state (Peng et al, 2013b;Wang et al, 2018); whereas CXCR6 shows an opposite expression pattern ; Thy-1, CD18, and NKG2D are widely expressed on both subsets . As CD49b + cNK cells lack CXCR6 and CD49a, the specific factors responsible for the tissue-residency of memory CD49b + cNK cells in the liver remain unclear.…”

“…MCMV-and cytokine-induced conventional memory NK cells exhibit similar migration patterns with T EM cells, which populate throughout the body; whereas recently defined tissue-resident memory ILCs mirror the generation and maintenance of T RM cells. Virusand hapten-induced memory CXCR6 + CD49a + NK cells and IL-7Rα + ILC1s selectively reside in the liver (Paust et al, 2010;Peng et al, 2013a;Wang et al, 2018). IL-33-induced memory-like ILC2s show long-term residency in the lung (Martinez-Gonzalez et al, 2016).…”

“…Innate lymphoid cells (ILCs), including natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue-inducer (LTi) cells, are a group of innate lymphocytes that confer early defense against pathogenic infections and tumor development (Cella et al, 2008;Cupedo et al, 2008;Sanos et al, 2008;Satoh-Takayama et al, 2008;Moro et al, 2009;Neill et al, 2010;Fuchs et al, 2013;Klose et al, 2014;Vivier et al, 2018). However, recent studies have uncovered the adaptive features of NK cells and other ILCs (O'Leary et al, 2006;Cooper et al, 2009;Sun et al, 2009;Peng et al, 2013a;Martinez-Gonzalez et al, 2016;Wang et al, 2018Wang et al, , 2019. Mouse cytomegalovirus (MCMV) infection induces the generation of memory Ly49H + NK cells (Sun et al, 2009), and cytokine stimulation with interleukin (IL)-12/15/18 mediates memory-like NK cell formation (Cooper et al, 2009).…”

“…Besides this type of memory NK cells, recently defined memory ILCs show long-term residency in peripheral tissue, but not in the circulation, and they are referred to as tissue-resident memory ILCs (Table 1). For example, hapten-induced memory NK cells and ILC1s are liver-resident (Paust et al, 2010;Peng et al, 2013a;Li et al, 2017;Wang et al, 2018), and IL-33-responsive ILC2s can acquire memory potential and persist in the lung (Martinez-Gonzalez et al, 2016). These new findings prompt us to reexamine the biology of ILCs and their roles in disease progression.…”