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The individual contribution of specific myeloid subsets such as CD1c+ conventional dendritic cells (cDC) to perpetuation of Rheumatoid Arthritis (RA) pathology remains unclear. In addition, the specific innate sensors driving pathogenic activation of CD1c+ cDCs in RA patients and their functional implications have not been characterized. Here, we assessed phenotypical, transcriptional and functional characteristics of CD1c+ and CD141+ cDCs and monocytes from the blood and synovial fluid of RA patients. Increased levels of CCR2 and the IgG receptor CD64 on circulating CD1c+ cDC associated with the presence of this DC subset in the synovial membrane in RA patients. Moreover, synovial CD1c+ cDCs are characterized by increased expression of proinflammatory cytokines and high abilities to induce pathogenic IFNγ+IL-17+ CD4+ T cells in vitro. Finally, we identified the crosstalk between Fcγ Receptors and NLRC4 as a new potential molecular mechanism mediating pathogenic activation, CD64 upregulation and functional specialization of CD1c+ cDCs in response to dsDNA-IgG in RA patients. E.M.G. was supported by Comunidad de Madrid Talento Program (2017-T1/BMD5396), Ramón y Cajal Program (RYC2018-024374-I), the MINECO RETOS program (RTI2018-097485-A-I00), La Caixa Foundation (HR20-00218), CIBERINF (CB21/13/00107) and the TV3 Marató (REDINCOV). C.D.A. was supported by Comunidad de Madrid Talento Program (2017-T1/BMD-5396). M.C.M was supported by the NIH (R21AI140930). HR17-00016 grant from “La Caixa Banking Foundation to F.S.M also supported the study. D.C-F. is supported by the Fellowship “la Caixa” Foundation LCF/BQ/DR19/11740010. A.T.M. was supported by a PhD fellowship from the Autonomous Region of Madrid (PEJD-2019-PRE/BMD-16851) and the RD21/0002/0027 grant. R.L. and G.H.B. were supported by PI18/00261 AND PI20/00349 grants from Ministerio de Ciencia e Innovación and Instituto de Salud Carlos III, respectively. O.P. was supported by the TV3 Marató (REDINCOV) and I.T. was funded by grant for the promotion of research studies master-UAM 2021. S.C. was supported by PI21/01474 grant from the Instituto de Salud Carlos III and co-funded by The European Regional Development Fund (ERDF). I.G.A was supported by RD21/0002/0027 and PI21/00526 grants from the Spanish MINECO and Instituto de Salud Carlos III and co-funded by The European Regional Development Fund (ERDF) “A way to make Europe. Sí

Background: Dysfunction of CD8+ T cells in people living with HIV-1 (PLWH) receiving anti-retroviral therapy (ART) has restricted the efficacy of dendritic cell (DC)-based immunotherapies against HIV-1. Heterogeneous immune exhaustion and metabolic states of CD8+ T cells might differentially associate with dysfunction. However, specific parameters associated to functional restoration of CD8+ T cells after DC treatment have not been investigated. Methods: We studied association of restoration of functional HIV-1-specific CD8+ T cell responses after stimulation with Gag-adjuvant-primed DC with ART duration, exhaustion, metabolic and memory cell subsets profiles. Findings: HIV-1-specific CD8+ T cell responses from a larger proportion of PLWH on long-term ART (more than 10 years; LT-ARTp) improved polyfunctionality and capacity to eliminate autologous p24+ infected CD4+ T cells in vitro. In contrast, functional improvement of CD8+ T cells from PLWH on short-term ART (less than a decade; ST-ARTp) after DC treatment was limited. This was associated with lower frequencies of central memory CD8+ T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolysis induction upon TCR activation. In contrast, CD8+ T cells from LT-ARTp showed increased frequencies of TIM3+ PD1− cells and preserved induction of glycolysis. Treatment of dysfunctional CD8+ T cells from ST-ARTp with combined anti-PD1 and anti-TIGIT antibodies plus a glycolysis promoting drug restored their ability to eliminate infected CD4+ T cells. Interpretation: Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines. Funding: NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants, NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants