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Tissue-resident memory CD8+ T cells serve as a first-line defense against many pathogens. In this issue of Immunity , Buquicchio et al. unveil the epigenomic landscapes of virus-specific CD8+ T cell subsets, highlighting common and organ-specific regulators driving their differentiation. [ABSTRACT FROM AUTHOR]

Mpox represents a persistent health concern with varying disease severity. Reinfections with mpox virus (MPXV) are rare, possibly indicating effective memory responses to MPXV or related poxviruses, notably vaccinia virus (VACV) from smallpox vaccination. We assessed cross-reactive and virus-specific CD4+ and CD8+ T cells in healthy individuals and mpox convalescent donors. Cross-reactive T cells were most frequently observed in healthy donors over 45 years. Notably, long-lived memory CD8+ T cells targeting conserved VACV/MPXV epitopes were identified in older individuals more than four decades after VACV exposure and exhibited stem-like characteristics, defined by T cell factor-1 (TCF-1) expression. In mpox convalescent donors, MPXV-reactive CD4+ and CD8+ T cells were more prevalent than in controls, demonstrating enhanced functionality and skewing toward effector phenotypes, which correlated with milder disease. Collectively, we report robust effector memory MPXV-specific T cell responses in mild mpox and long-lived TCF-1+ VACV/MPXV-specific CD8+ T cells decades after smallpox vaccination. [Display omitted] • Cross-reactive T cells against MPXV are found in many unexposed adults • TCF-1+ VACV-specific CD8+ T cells persist >4 decades after smallpox vaccination • MPXV-specific CD4+ and CD8+ T cells acquire functional effector phenotypes upon mpox • MPXV-specific CD8+ T cells from patients with mild mpox show high effector potential Adamo et al. demonstrate that MPXV-reactive T cells are present in many healthy blood donors—especially in older individuals. Smallpox-vaccinated individuals maintain very long-lived resting memory T cells that are cross-reactive to MPXV, whereas those recovering from mpox develop polyfunctional effector T cell responses associated with milder disease outcomes. [ABSTRACT FROM AUTHOR]

Lymphocyte migration is essential for adaptive immune surveillance. However, our current understanding of this process is rudimentary, because most human studies have been restricted to immunological analyses of blood and various tissues. To address this knowledge gap, we used an integrated approach to characterize tissue-emigrant lineages in thoracic duct lymph (TDL). The most prevalent immune cells in human and non-human primate efferent lymph were T cells. Cytolytic CD8+ T cell subsets with effector-like epigenetic and transcriptional signatures were clonotypically skewed and selectively confined to the intravascular circulation, whereas non-cytolytic CD8+ T cell subsets with stem-like epigenetic and transcriptional signatures predominated in tissues and TDL. Moreover, these anatomically distinct gene expression profiles were recapitulated within individual clonotypes, suggesting parallel differentiation programs independent of the expressed antigen receptor. Our collective dataset provides an atlas of the migratory immune system and defines the nature of tissue-emigrant CD8+ T cells that recirculate via TDL. • Comprehensive map of the human immune system in thoracic duct • Non-cytolytic effector memory CD8+ T cells primarily recirculate via thoracic duct • Cytolytic CD8+ T cells confined to intravascular circulation at steady state • Individual antigen-specific clones exhibit distinct migratory and functional capabilities Buggert et al. provide a core signature that defines humantissue-emigrant CD8+ T cells under homeostatic conditions. They observe that cytolytic effector memory CD8+ T cells are primarily confined to peripheral blood and almost absent in thoracic duct lymph, indicating that distinct effector memory populations surveil blood and tissues. [ABSTRACT FROM AUTHOR]

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8 + T cells and exhausted CD8 + T cell (T EX ) clones. Focused analyses of T EX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor T EX , which synergizes with anti-PD-1 to reinvigorate T EX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies., Competing Interests: Declaration of interests A.C.H. performed consulting work for Immunai and received research funding from Bristol Myers Squibb and Merck. R.S.H. has performed consulting work for Bristol Myers Squibb (exclusive of the current work). T.C.M. received honorarium for Scientific Advisory Board participation from: BMS, GigaGen, Merck, Pliant, Pfizer. G.C.K. is on the Merck Advisory Board. J.W. consulted for and have received less than $10,000 per annum from Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, Moderna, ImCheck, Sellas, Evaxion, Pfizer, Regeneron, and EMD Serono and received $10–$25,000 from BMS for membership on advisory boards. J.W. also holds equity in Biond, Evaxion, OncoC4, and Instil Bio, and on scientific advisory boards for CytomX, Incyte, ImCheck, Biond, Sellas, Instil Bio, OncoC4, and NexImmune and remunerated between $10,000–$50,000. In addition, J.W. is named on a patent filed by Moffitt Cancer Center on an ipilimumab biomarker and on TIL preparation and also on a PD-1 patent filed by Biodesix; J.W. receives less than $6000 in royalties. D.B., E.K., and C.S. were employed by Immunai when engaged in this project. S.G. and D.T. are employees of BMS. C.A. is a consultant for Biotherapy Partners., (Copyright © 2024 Elsevier Inc. All rights reserved.)

T cells are critical in mediating the early control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection. However, it remains unknown whether memory T cells can effectively cross-recognize new SARS-CoV-2 variants with a broad array of mutations, such as the emergent hypermutated BA.2.86 variant. Here, we report in two separate cohorts, including healthy controls and individuals with chronic lymphocytic leukemia, that SARS-CoV-2 spike-specific CD4 + and CD8 + T cells induced by prior infection or vaccination demonstrate resilient immune recognition of BA.2.86. In both cohorts, we found largely preserved SARS-CoV-2 spike-specific CD4 + and CD8 + T cell magnitudes against mutated spike epitopes of BA.2.86. Functional analysis confirmed that both cytokine expression and proliferative capacity of SARS-CoV-2 spike-specific T cells to BA.2.86-mutated spike epitopes are similarly sustained. In summary, our findings indicate that memory CD4 + and CD8 + T cells continue to provide cell-mediated immune recognition to highly mutated emerging variants such as BA.2.86., Competing Interests: Declaration of interests A.S. is a consultant for AstraZeneca Pharmaceuticals; Calyptus Pharmaceuticals, Inc; Darwin Health; EmerVax; EUROIMMUN; F. Hoffman-La Roche Ltd; Fortress Biotech; Gilead Sciences; Granite Bio.; Gritstone Oncology; Guggenheim Securities; Moderna; Pfizer; RiverVest Venture Partners; and Turnstone Biologics. A.G. is a consultant for Pfizer. A.S. has filed for patent protection for various aspects of T cell epitope and vaccine design work. M.B. is a consultant and has received honoraria from Oxford Immunotec, MSD, BMS, Pfizer, and Mabtech. S.A. has received honoraria for lectures and educational events, not related to this work, from Gilead, AbbVie, MSD, and Biogen and reports grants from Gilead and AbbVie., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Many immunocompromised patients mount suboptimal humoral immunity after SARS-CoV-2 mRNA vaccination. Here, we assessed the single-cell profile of SARS-CoV-2-specific T cells post-mRNA vaccination in healthy individuals and patients with various forms of immunodeficiencies. Impaired vaccine-induced cell-mediated immunity was observed in many immunocompromised patients, particularly in solid-organ transplant and chronic lymphocytic leukemia patients. Notably, individuals with an inherited lack of mature B cells, i.e., X-linked agammaglobulinemia (XLA) displayed highly functional spike-specific T cell responses. Single-cell RNA-sequencing further revealed that mRNA vaccination induced a broad functional spectrum of spike-specific CD4 + and CD8 + T cells in healthy individuals and patients with XLA. These responses were founded on polyclonal repertoires of CD4 + T cells and robust expansions of oligoclonal effector-memory CD45RA + CD8 + T cells with stem-like characteristics. Collectively, our data provide the functional continuum of SARS-CoV-2-specific T cell responses post-mRNA vaccination, highlighting that cell-mediated immunity is of variable functional quality across immunodeficiency syndromes., Competing Interests: Declaration of interests M.B. is a consultant for Oxford Immunotec. A.S. is a consultant for Gritstone, Flow Pharma, Arcturus, Immunoscape, CellCarta, Oxford Immunotech, and Avalia. A.S. has filed for patent protection for various aspects of T cell epitope and vaccine design work., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Immunocompromised individuals are highly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Whether vaccine-induced immunity in these individuals involves oral cavity, a primary site of infection, is presently unknown., Methods: Immunocompromised patients (n = 404) and healthy controls (n = 82) participated in a prospective clinical trial (NCT04780659) encompassing two doses of the mRNA BNT162b2 vaccine. Primary immunodeficiency (PID), secondary immunodeficiencies caused by human immunodeficiency virus (HIV) infection, allogeneic hematopoietic stem cell transplantation (HSCT)/chimeric antigen receptor T cell therapy (CAR-T), solid organ transplantation (SOT), and chronic lymphocytic leukemia (CLL) patients were included. Salivary and serum immunoglobulin G (IgG) reactivities to SARS-CoV-2 spike were measured by multiplex bead-based assays and Elecsys anti-SARS-CoV-2 S assay., Findings: IgG responses to SARS-CoV-2 spike antigens in saliva in HIV and HSCT/CAR-T groups were comparable to those of healthy controls after vaccination. The PID, SOT, and CLL patients had weaker responses, influenced mainly by disease parameters or immunosuppressants. Salivary responses correlated remarkably well with specific IgG titers and the neutralizing capacity in serum. Receiver operating characteristic curve analysis for the predictive power of salivary IgG yielded area under the curve (AUC) = 0.95 and positive predictive value (PPV) = 90.7% for the entire cohort after vaccination., Conclusions: Saliva conveys vaccine responses induced by mRNA BNT162b2. The predictive power of salivary spike IgG makes it highly suitable for screening vulnerable groups for revaccination., Funding: Knut and Alice Wallenberg Foundation, Erling Perssons family foundation, Region Stockholm, Swedish Research Council, Karolinska Institutet, Swedish Blood Cancer Foundation, PID patient organization of Sweden, Nordstjernan AB, Center for Medical Innovation (CIMED), Swedish Medical Research Council, and Stockholm County Council (ALF)., Competing Interests: S. Mielke received honoraria via his institution from Celgene/BMS, Novartis, Gilead/Kite, and DNA Prime for lectures and educational events and as a member and/or head of data safety monitoring boards from Miltenyi Biotec and Immunicum outside the submitted work. K.L. reports grants from Knut and Alice Wallenberg Foundation VC-2021-0018. H.-G.L. reports grants from Knut and Alice Wallenberg Foundation and Nordstjernan AB for studies on COVID-19. P.L. reports grants from Pfizer, grants from MSD, grants and personal fees from Takeda, personal fees from AiCuris, and personal fees from OctaPharma, Enanta Pharmaceuticals, and BMS outside the submitted work. S.A. has received honoraria for lectures and educational events, not related to this work, from Gilead, AbbVie, MSD, Biogen, and Netdoktor and reports grants from Knut and Alice Wallenberg Foundation for this study. M.S.C. reports grants from CIMED for this study and is co-founder of SVF AB., (© 2022 The Author(s).)

SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. Here, we systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19. Acute-phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent-phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative exposed family members and convalescent individuals with a history of asymptomatic and mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits broadly directed and functionally replete memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Elimination of lymphoid tissue reservoirs is a key component of HIV eradication strategies. CD8 + T cells play a critical role in control of HIV, but their functional attributes in lymph nodes (LNs) remain unclear. Here, we show that memory, follicular CXCR5 + , and HIV-specific CD8 + T cells from LNs do not manifest the properties of cytolytic CD8 + T cells. While the frequency of follicular CXCR5 + CD8 + T cells was strongly inversely associated with peripheral viremia, this association was not dependent on cytolytic CXCR5 + CD8 + T cells. Moreover, the poor cytolytic activity of LN CD8 + T cells was linked to a compartmentalized dissociation between effector programming and the transcription factor T-bet. In line with this, activation of LN CD8 + T cells only partially induced the acquisition of cytolytic functions relative to peripheral blood CD8 + T cells. These results suggest that a state of immune privilege against CD8 + T cell-mediated cytolysis exists in lymphoid tissue, potentially facilitating the persistence of HIV., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)