PMC

During viral infection, NK cells and CD8⁺ T cells mount specific responses following antigen receptor triggering. T cell receptor (TCR)-MHC interactions (signal 1), co-stimulation (including CD28, signal 2), and pro-inflammatory cytokines (including interleukin (IL)-12 and type I interferons (IFNs), signal 3) are the three signals thought to promote the activation and clonal expansion of naïve CD8⁺ T cells. Similarly, naïve NK cells receive signals via activating receptors, co-stimulatory receptors (including DNAM-1), and pro-inflammatory cytokine receptors (including IL-12R, IL-18R, and IL-33R).

(Left panel) Mature NK (mNK) cells co-express the Tbox transcription factors T-bet and Eomes, and require both for their development. mNK cells also express the marker CD49b (α2β1 integrin), but typically not CD49a (α1β1 integrin), during homeostasis or following adoptive transfer. mNK cells were found to re-circulate in parabiotic mice, and can be found in the spleen and most peripheral organs. (Middle panel) CXCR6⁺ NK cells or ILC1 cells in the liver express T-bet, but not Eomes, during homeostasis or following adoptive transfer. These cells require T-bet, but not Eomes, for their development. Unlike mNK, this liver population expresses CD49a but not CD49b. CXCR6⁺ liver NK cells were found to be tissue resident in parabiotic mice, and selectively home to the liver following adoptive transfer. (Right panel) NK or ILC1 found in the small intestine lamina propria do not express Eomes, nor require its expression for their development. These cells require T-bet for their development, and co-express CD49a and the interleukin 7 receptor (IL-7R). In the steady state, ILC1 are less cytotoxic than mNK, but produce IFN-γ following cytokine stimulation. Whether or not these tissue-localized NK or ILC1 cells are tissue-resident or can acquire the property of long-lived memory remains unknown.

Upon exposure to cognate antigen, naïve CD8⁺ T cells clonally expand and differentiate into effector cells during the “expansion” phase. This first phase is followed by a rapid “contraction” phase when the vast majority of effector CD8⁺ T cells undergo apoptosis to form a small, but stable, pool of surviving cells that then enter the third “memory” phase. Memory CD8⁺ T cells persist throughout the host organs and maintain their longevity through self-renewal until subsequent encounter with their cognate antigen, when they exhibit enhanced effector function and host protection. Using an experimental system in which Ly49H⁺ NK cells are adoptively transferred into mice lacking this receptor, robust antigen-driven expansion of these Ly49H⁺ cells is observed following MCMV infection. Expanded effector NK cells undergo a slower and sustained contraction phase, similar to activated CD4⁺ T cells, to establish a long-lived and self-renewing “memory” pool of antigen-specific NK cells that can be recovered many months following infection in a variety of peripheral tissues.

Antigen-dependent memory NK cells: (Far left panel) Viral-induced NK cell memory is generated during MCMV infection after the cognate recognition of the m157 MCMV protein on infected cells by the activating Ly49H receptor. Memory generation is promoted by IL-12, IL-18, and IL-33 receptor signaling and co-stimulatory signals by DNAM-1, while memory NK cell survival is controlled by BNIP3 and BNIP3L-mediated mitophagy (shown in green). Memory NK cell survival is negatively regulated by BIM, Noxa, and SOCS1 (shown in red). (Middle left panel) Sensitization with haptens or specific antigens, in conjunction with CXCL16, IFNs, and IL-12 is required to generate CXCR6⁺ memory NK cells. These phenotypically distinct cells may be selected by the cognate recognition of the hapten, a hapten-modified self-protein, or virus-like particle, and develop into memory NK cells, although the receptors responsible for the antigen specificity have not been identified. Antigen-independent memory NK cells: (Middle right panel) Cytokine-induced memory NK cells are generated after exposure to IL-12, IL-15, and IL-18. These cells apparently do not require activating NK receptor triggering for their longevity or enhanced IFN-γ production upon re-stimulation; however, the mechanisms governing their longevity are unknown. (Far right panel) Mature NK cells undergo homeostatic proliferation when transferred into recipient Rag2 × Il2rγ-deficient mice. These NK cells persist and are long-lived, similar to MCMV-induced memory NK cells. The mechanisms driving NK cell homeostatic proliferation and survival in this model remain unknown.