Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.

T cell receptor (TCR) γδ-expressing T lymphocytes compose evolutionarily conserved cells with paradoxical features. On the one hand, clonally expanded γδ T cells with unique specificities typify adaptive immunity. Conversely, large TCRγδ+ intraepithelial lymphocyte (γδ IEL) compartments exhibit limited TCR diversity and effect rapid, innate-like tissue surveillance. The development of several γδ IEL compartments depends upon epithelial Btnl/BTNL (butyrophilin-like) genes, which are members of the B7-superfamily of T cell co-stimulators. Here we show that Btnl/BTNL responsiveness is mediated by germline-encoded motifs within the cognate TCRVγ chains of mouse and human γδ IEL. This contrasts with diverse antigen recognition by clonally-restricted complementarity-determining regions (CDRs) 1-3 of TCRγδ. Hence, TCRγδ intrinsically combines innate and adaptive immunity by utilizing spatially distinct regions to discriminate non-clonal agonist-selecting elements from clone-specific ligands. The broader implications for antigen receptor biology are considered.

SignificanceAlthough gamma delta (γδ) T cells compose an evolutionarily conserved third lineage of diversified lymphocytes, alongside αβ T cells and B cells, they can seem overtly different across species and tissues. Thus, human blood γδ cells show butyrophilin (BTN)3A1-dependent responses to metabolites (“phosphoantigens”) not seen by rodent γδ cells, whereas some rodent, γδ-rich compartments, notably in the skin, lack obvious human counterparts. Recently, however, mouse and human intraepithelial gut γδ cells were found to be regulated by pairings of BTN-like genes. This study now shows that BTN3A1 also functions as a pairing, with its subcellular trafficking and optimal activity both regulated by BTN3A2. Hence, seemingly diverse γδ cell biologies across species and tissues are underpinned by conserved mechanisms.

Graphical Abstract Highlights d BTNL3 binds directly and specifically to Vg4 + TCRs via its IgV domain d The superantigen-like binding mode focuses on germlineencoded TCR regions d In contrast, gd TCR binding to a clonally restricted antigen is CDR3-mediated d Mutagenesis indicates parallels with BTN3A1-mediated activation of Vg9Vd2 T cells SUMMARY Butyrophilin (BTN) and butyrophilin-like (BTNL/Btnl) heteromers are major regulators of human and mouse gd T cell subsets, but considerable contention surrounds whether they represent direct gd T cell receptor (TCR) ligands. We demonstrate that the BTNL3 IgV domain binds directly and specifically to a human Vg4 + TCR, ''LES'' with an affinity ($15-25 mM) comparable to many ab TCR-peptide major histocompatibility complex interactions. Mutations in germline-encoded Vg4 CDR2 and HV4 loops, but not in somatically recombined CDR3 loops, drastically diminished binding and T cell responsiveness to BTNL3-BTNL8-expressing cells. Conversely, CDR3g and CDR3d loops mediated LES TCR bindingto endothelial protein C receptor, a clonally restricted autoantigen, with minimal CDR1, CDR2, or HV4 contributions. Thus, the gd TCR can employ two discrete binding modalities: a non-clonotypic, superantigenlike interaction mediating subset-specific regulation by BTNL/BTN molecules and CDR3-dependent, antibody-like interactions mediating adaptive gd T cell biology. How these findings might broadly apply to gd T cell regulation is also examined.

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Person-to-person transmission of SARS-CoV-2 virus has triggered a global emergency because of its potential to cause life-threatening Covid-19 disease. By comparison to pauci-symptomatic virus clearance by most individuals, Covid-19 has been proposed to reflect insufficient and/or pathologically exaggerated immune responses. Here we identify a consensus peripheral blood immune signature across 63 hospital-treated Covid-19 patients who were otherwise highly heterogeneous. The core signature conspicuously blended adaptive B cell responses typical of virus infection or vaccination with discrete traits hitherto associated with sepsis, including monocyte and dendritic cell dampening, and hyperactivation and depletion of discrete T cell subsets. This blending of immuno-protective and immuno-pathogenic potentials was exemplified by near-universal CXCL10/IP10 upregulation, as occurred in SARS1 and MERS. Moreover, specific parameters including CXCL10/IP10 over-expression, T cell proliferation, and basophil and plasmacytoid dendritic cell depletion correlated, often prognostically, with Covid-19 progression, collectively composing a resource to inform SARS-CoV-2 pathobiology and risk-based patient stratification.

In the version of this article initially published, the middle initial was missing from author name 'Joshua Freedman' (with Author contribution initials 'J.F. '). The correct author name is 'Joshua D. Freedman' , and the corresponding Author contribution initials are 'J.D.F. '. The error has been corrected in the HTML and PDF versions of the article.

Whereas pathogen-specific T and B cells are a primary focus of interest during infectious disease, we have used COVID-19 to ask whether their emergence comes at a cost of broader B cell and T cell repertoire disruption. We applied a genomic DNA-based approach to concurrently study the immunoglobulin-heavy (IGH) and T cell receptor (TCR) β and δ chain loci of 95 individuals. Our approach detected anticipated repertoire focusing for the IGH repertoire, including expansions of clusters of related sequences temporally aligned with SARS-CoV-2–specific seroconversion, and enrichment of some shared SARS-CoV-2–associated sequences. No significant age-related or disease severity–related deficiencies were noted for the IGH repertoire. By contrast, whereas focusing occurred at the TCRβ and TCRδ loci, including some TCRβ sequence–sharing, disruptive repertoire narrowing was almost entirely limited to many patients aged older than 50 y. By temporarily reducing T cell diversity and by risking expansions of nonbeneficial T cells, these traits may constitute an age-related risk factor for COVID-19, including a vulnerability to new variants for which T cells may provide key protection.