Rapid and efficient generation of regulatory T cells to commensal antigens in the periphery

SummaryCommensal bacteria shape the colonic regulatory T (Treg) cell population required for intestinal tolerance. However, little is known about this process. Here, we use the transfer of naive commensal-reactive transgenic T cells expressing colonic Treg T cell receptors (TCRs) to study peripheral Treg (pTreg) cell development in normal hosts. We found that T cells were activated primarily in the distal mesenteric lymph node. Treg cell induction was rapid, generating >40% Foxp3+ cells 1 week after transfer. Contrary to prior reports, Foxp3+ cells underwent the most cell divisions, demonstrating that pTreg cell generation can be the dominant outcome from naive T cell activation. Moreover, Notch2-dependent, but not Batf3-dependent, dendritic cells were involved in Treg cell selection. Finally, neither deletion of the conserved nucleotide sequence 1 (CNS1) region in Foxp3 nor blockade of TGF-β (transforming growth factor-β)-receptor signaling completely abrogated Foxp3 induction. Thus, these data show that pTreg cell selection to commensal bacteria is rapid, is robust, and may be specified by TGF-β-independent signals

Gut Helicobacter presentation by multiple dendritic cell subsets enables context-specific regulatory T cell generation

Generation of tolerogenic peripheral regulatory T (pTreg) cells is commonly thought to involve CD10

Characterizing Regulatory T Cell Differentiation to Bacterial Antigens in the Gut

Gut commensal bacteria shape the colonic regulatory T (Treg) cell population required for intestinal homeostasis. However, little is known about this process. Here, we use the transfer of naïve transgenic T cells expressing colonic Treg TCRs to study gut Treg cell development in normal hosts. T cells were initially activated primarily in the distal mesenteric lymph node; Treg cell differentiation started within 2 days and with Foxp3+ cells in the most divided population, demonstrating that peripheral Treg cell generation can be the dominant outcome from naïve T cell activation. Various cell intrinsic and cell extrinsic elements are needed for this conversion. TGFβ is canonically said to be required for pTreg development, but TGFβ-receptor blockade in transferred cells only reduced, but did not abrogate Foxp3 expression. Additionally, cell-intrinsic signaling through the CNS1 region in the Foxp3 locus was required for early, but not late, Foxp3 induction. Though environmental influences also affect pTreg development, and decreased conversion was seen in C. rodentium infection and DSS induced inflammation, a regulatory fate was still the dominant differentiation outcome. Additionally, pTreg conversion is partially reliant on Notch2-dependent DCs during homeostasis

Risk of COVID-19 after natural infection or vaccinationResearch in context

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health