Highlights d Longitudinal analysis of multifaceted immune memory following mild COVID-19 d Antibodies capable of neutralizing virus persist for at least 3 months in most subjects d Virus-specific memory B and T cells display hallmarks of anti-viral immunity d MBCs increase in number and express antibodies capable of neutralizing SARS-CoV-2

DAP12 is an ITAM-containing adapter that associates with receptors in myeloid and NK cells. DAP12-associated receptors can give activation signals leading to cytokine production; however, in some situations, DAP12 inhibits cytokine production stimulated through TLRs and FcRs. Here we show that Triggering Receptor Expressed on Myeloid cells (TREM)-2 is responsible for the DAP12-mediated inhibition in mouse macrophages. A chimeric receptor composed of the extracellular domain of TREM-2 and the cytoplasmic domain of DAP12 inhibited the TLR- and FcR-induced TNF production of DAP12-deficient macrophages, whereas a TREM-1 chimera did not. In wild-type macrophages, TREM-2 knockdown increased TLR-induced TNF production. A TREM-2 Fc fusion protein bound to macrophages, indicating that macrophages express a TREM-2 ligand. Thus, the interaction of TREM-2 and its ligand results in an inhibitory signal that can reduce the inflammatory response.

DAP12 is a signaling adaptor containing an immunoreceptor tyrosine-based activation motif (ITAM) that pairs with receptors on myeloid cells and natural killer cells. We examine here the responses of mice lacking DAP12 to stimulation through Toll-like receptors (TLRs). Unexpectedly, DAP12-deficient macrophages produced higher concentrations of inflammatory cytokines in response to a variety of pathogenic stimuli. Additionally, macrophages deficient in spleen tyrosine kinase (Syk), which signals downstream of DAP12, showed a phenotype identical to that of DAP12-deficient macrophages. DAP12-deficient mice were more susceptible to endotoxic shock and had enhanced resistance to infection by the intracellular bacterium Listeria monocytogenes. These data suggest that one or more DAP12-pairing receptors negatively regulate signaling through TLRs.TLRs are pattern recognition receptors used by cells of the innate immune system to detect the presence of a wide variety of pathogens. The 11 TLRs known in mammals allow the innate immune system to respond to a range of pathogen products, including proteins, lipoproteins, polysaccharides and nucleic acids 1 . In macrophages, TLR ligation leads to the production of proinflammatory cytokines, including tumor necrosis factor (TNF), interleukin 6 (IL-6) and IL-12. This cytokine production is crucial to a productive innate and adaptive immune response, leading to pathogen clearance. Additionally, when cytokine production is not properly regulated, inflammatory disorders such as rheumatoid arthritis or septic shock may result.The TLR signaling pathway differs somewhat for each TLR 1 . In common are a series of signaling proteins beginning with the adaptor protein MyD88, which associates with TLRs through homotypic interactions of Toll-IL-1 receptor (TIR) domains. When associated with a TLR, MyD88 recruits members of the IL-1 receptor-associated kinase (IRAK) family of serine-threonine kinases, which then phosphorylate and activate the ubiquitin ligase TNF receptor-associated factor 6 (TRAF6). Activation of TRAF6 leads to activation of the three mitogen-activated protein kinase (MAPK) pathways, p38 MAPK, ERK and JNK, and results in translocation of the transcription factor NF-κB into the nucleus. This occurs through the phosphorylation and degradation of IκBα, a protein that binds and retains NF-κB in the cytoplasm in resting cells. NF-κB is a key transcription factor in the induction of proinflammatory cytokines in macrophages, including TNF, IL-6 and IL-12 p40. Some TLRs also use other TIR-containing adaptor proteins, including TIRAP (also called Mal), TRIF (also Correspondence should be addressed to L.L.L. ( lanier@itsa.ucsf.edu).. Note: Supplementary information is available on the Nature Immunology website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access RESULTS Increased cytokine production by DAP12-deficient macrophagesTo investigate the role of macrophage DAP12-associated receptors in the responses to...

NKG2D is an activating receptor on CD8(+) T cells and NK cells that has been implicated in immunity against tumors and microbial pathogens. Here we show that RAE-1 is present in prediabetic pancreas islets of NOD mice and that autoreactive CD8(+) T cells infiltrating the pancreas express NKG2D. Treatment with a nondepleting anti-NKG2D monoclonal antibody (mAb) during the prediabetic stage completely prevented disease by impairing the expansion and function of autoreactive CD8(+) T cells. These findings demonstrate that NKG2D is essential for disease progression and suggest a new therapeutic target for autoimmune type I diabetes.