Neonatal LTßR signaling is required for the accumulation of eosinophils in the inflamed adult mesenteric lymph node.

Although eosinophils are important contributors to mucosal immune responses, mechanisms that regulate their accumulation in mucosal-associated lymphoid tissues remain ill-defined. Combining bone marrow chimeras and pharmacological inhibition approaches, here we find that lymphotoxin-beta receptor (LTßR) signaling during the neonatal period is required for the accumulation of eosinophils in the mesenteric lymph nodes (MLN) during an enteric viral infection in adult male and female mice. We demonstrate that MLN stromal cells express genes that are important for eosinophil migration and survival, such as Ccl-11 (eotaxin-1), Ccl7, Ccl9, and Cxcl2, and that expression of most of these genes is downregulated as a consequence of neonatal LTßR blockade. We also find that neonatal LTßR signaling is required for the generation of a rotavirus-specific IgA antibody response in the adult MLN, but eosinophils are dispensable for this response. Collectively, our studies reveal a role for neonatal LTßR signaling in regulating eosinophil numbers in the adult MLN.

Investigation of an outbreak of COVID-19 among U.S. military personnel and beneficiaries stationed in the Republic of Korea, June-July 2021.

On 28 May 2021, leisure travel restrictions in place to control coronavirus disease 2019 (COVID-19) were eased among vaccinated U.S. military personnel and beneficiaries stationed in South Korea (USFK) allowing access to bars and clubs which were off limits. We describe results from an investigation of the largest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak as of November 2021 among USFK personnel following this change in policy. Data such as SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) test results, demographic characteristics, symptom and vaccination histories, and genome sequences were analyzed. Of a total 207 new cases of COVID-19 diagnosed among USFK members from 15 June to 27 July 2021, 113 (57%) eligible cases were fully vaccinated, of whom 86 (76%) were symptomatic. RT-PCR cycling threshold values were similar among vaccinated and unvaccinated members. Whole genomic sequencing of 54 outbreak samples indicated all infections were due to the Delta variant. Phylogenetic analysis revealed two sources of SARS-CoV-2 accounted for 41% of infections among vaccinated and unvaccinated members. Vaccinated personnel were not at risk of severe illness; however, 86% experienced symptoms following infection. There were no hospitalizations among COVID-19 cases, most of whom were young military service members. Rescinded restrictions were reinstated to control the outbreak. Masking was mandated among all personnel predating U.S. national recommendations for indoor masking in high COVID-19 transmission areas. Increased vaccination with continued vigilance and extension of COVID-19 mitigation measures are warranted to contain the spread of SARS-CoV-2 variants of concern.

Early-life programming of mesenteric lymph node stromal cell identity by the lymphotoxin pathway regulates adult mucosal immunity.

Redundant mechanisms support immunoglobulin A (IgA) responses to intestinal antigens. These include multiple priming sites [mesenteric lymph nodes (MLNs), Peyer's patches, and isolated lymphoid follicles] and various cytokines that promote class switch to IgA, even in the absence of T cells. Despite these backup mechanisms, vaccination against enteric pathogens such as rotavirus has limited success in some populations. Genetic and environmental signals experienced during early life are known to influence mucosal immunity, yet the mechanisms for how these exposures operate remain unclear. Here, we used rotavirus infection to follow antigen-specific IgA responses through time and in different gut compartments. Using genetic and pharmacological approaches, we tested the role of the lymphotoxin (LT) pathway-known to support IgA responses-at different developmental stages. We found that LT-ß receptor (LTßR) signaling in early life programs intestinal IgA responses in adulthood by affecting antibody class switch recombination to IgA and subsequent generation of IgA antibody-secreting cells within an intact MLN. In addition, early-life LTßR signaling dictates the phenotype and function of MLN stromal cells to support IgA responses in the adult. Collectively, our studies uncover new mechanistic insights into how early-life LTßR signaling affects mucosal immune responses during adulthood.

The H2B deubiquitinase Usp22 promotes antibody class switch recombination by facilitating non-homologous end joining.

Class switch recombination (CSR) has a fundamental function during humoral immune response and involves the induction and subsequent repair of DNA breaks in the immunoglobulin (Ig) switch regions. Here we show the role of Usp22, the SAGA complex deubiquitinase that removes ubiquitin from H2B-K120, in the repair of programmed DNA breaks in vivo. Ablation of Usp22 in primary B cells results in defects in γH2AX and impairs the classical non-homologous end joining (c-NHEJ), affecting both V(D)J recombination and CSR. Surprisingly, Usp22 depletion causes defects in CSR to various Ig isotypes, but not IgA. We further demonstrate that IgG CSR primarily relies on c-NHEJ, whereas CSR to IgA is more reliant on the alternative end joining pathway, indicating that CSR to different isotypes involves distinct DNA repair pathways. Hence, Usp22 is the first deubiquitinase reported to regulate both V(D)J recombination and CSR in vivo by facilitating c-NHEJ.