T Cell Regulation of Antibody Responses to Infection and Immunization

T follicular helper (Tfh) cells are the conventional drivers of protective, germinal center (GC)-based antiviral antibody responses. However, loss of Tfh cells and GCs has been observed in patients with severe COVID-19. As T cell-B cell interactions and immunoglobulin class switching still occur in these patients, non-canonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both Tfh-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Even though Tfh-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high-affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern. Indeed, we found by epitope mapping and BCR sequencing that Tfh cells focused the B cell response and therefore, in the absence of Tfh cells, a more diverse clonal repertoire was maintained. These data support a new paradigm for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation.Furthermore, we sought to reconcile the roles of Tfh cell-derived IL-4 as both a pro-survival factor for highly proliferative GC B cells as well as a switch factor for IgE and IgG1. Due to its potent effects on B cell proliferation and differentiation, IL-4 is considered a canonical Tfh cell cytokine, produced even during antimicrobial responses that elicit little IgG1 and no IgE. However, given that IL-4 is also a switch factor that is sufficient for IgE induction, this raises the question of how Tfh cells produce IL-4 during type 1 immune responses without aberrantly inducing IgE. We first clarified the role of Tfh cell-derived IL-4 during type 1 immune responses, finding that it was required for IgG1 switching in response to immunization with lipopolysaccharide and haptenated protein antigen as well as influenza A virus infection; however, GC B cell formation and plasmablast differentiation were unaffected by the loss of IL-4 from Tfh cells. In addition, we found that Tfh cells during type 1 immune responses generated minimal IL-4 protein, with levels of IL-4 tightly regulated by both transcriptional and post-transcriptional mechanisms. These data support the role of Tfh cell-derived IL-4 as a rheostat for the appropriate induction of IgG1 versus IgE antibodies during type 1 and type 2 immune responses, rather than as a pro-survival factor for GC B cells. Finally, when public health officials raised concerns about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating COVID-19 at the start of the pandemic, we sought to determine whether and how NSAIDs could affect COVID-19 pathogenesis. NSAIDs affect the production of prostaglandins, which play diverse biological roles in homeostasis and inflammatory responses. Thus, it is plausible that NSAIDs could affect COVID-19 pathogenesis in multiple ways, including modifying expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2; regulating replication of SARS-CoV-2 in host cells; and modulating the immune response to SARS-CoV-2. We found that NSAID treatment had no effect on ACE2 expression, viral entry, or viral replication. However, NSAIDs did affect the immune response to SARS-CoV-2 by impairing the production of proinflammatory cytokines as well as early neutralizing antibodies. Our findings therefore indicate that NSAID treatment may affect COVID-19 outcomes by dampening the inflammatory response and the production of protective antibodies, which also has implications for NSAID use during SARS-CoV-2 vaccination

SJS/TEN 2019: From science to translation.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs

NextGen Voices: Quality mentoring

In her Working Life, “Paying it forward as a mentor” (3 August, p. 522),B. Abderrahman describes how a mentor’s encouragement can help shapea career. She then explains how her positive mentorship experienceinspired her to mentor others. We asked young scientists to describe onequality of a mentor you’ve had that you will try to emulate when youbecome a mentor yourself. Respondents from around the world wrotein appreciation of their patient, honest, humble, and supportive

\u3ci\u3eDrosophila\u3c/i\u3e Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu