The continuing story of T‐cell independent antibodies

Allman, David; Wilmore, Joel R.; Gaudette, Brian T.

doi:10.1111/imr.12754

Cited by 80 publications

(61 citation statements)

References 79 publications

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“…The SARS-CoV-2 virion does not contain classic T cell-independent antigens, which are typically rigid arrays of 30 or more repeated epitopes optimally separated by 5–10 nm such as those present on vesicular stomatitis virus 14 15 . However, there is evidence that SARS-CoV-2 patients mount extrafollicular B cell responses 16 , 17 , a type of response that has been shown in mouse studies to produce IgM memory B cells and also IgG class-switched memory B cells in a T cell-independent manner 18 , 19 . In that regard most of the mice in all of the groups in this study mounted anamnestic IgM responses ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Recovery from acute SARS-CoV-2 infection and development of anamnestic immune responses in T cell-depleted rhesus macaques

Hasenkrug

Feldmann

Myers

et al. 2021

Preprint

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Severe COVID-19 has been associated with T cell lymphopenia 1,2, but no causal effect of T cell deficiency on disease severity has been established. To investigate the specific role of T cells in recovery from SARS-CoV-2 infections we studied rhesus macaques that were depleted of either CD4+, CD8+ or both T cell subsets prior to infection. Peak virus loads were similar in all groups, but the resolution of virus in the T cell-depleted animals was slightly delayed compared to controls. The T cell-depleted groups developed virus-neutralizing antibody responses and also class-switched to IgG. When re-infected six weeks later, the T cell-depleted animals showed anamnestic immune responses characterized by rapid induction of high-titer virus-neutralizing antibodies, faster control of virus loads and reduced clinical signs. These results indicate that while T cells play a role in the recovery of rhesus macaques from acute SARS-CoV-2 infections, their depletion does not induce severe disease, and T cells do not account for the natural resistance of rhesus macaques to severe COVID-19. Neither primed CD4+ or CD8+ T cells appeared critical for immunoglobulin class switching, the development of immunological memory or protection from a second infection.

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Section: Discussionmentioning

confidence: 99%

Recovery from acute SARS-CoV-2 infection and development of anamnestic immune responses in T cell-depleted rhesus macaques

Hasenkrug

Feldmann

Myers

et al. 2021

Preprint

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“…In mice, early primary antiviral responses are mediated by extrafollicular (EF) differentiation of naive B cells into short-lived ASCs independent of traditional germinal center incorporation 11 . While EF responses in different models are heterogeneous in their requirement for T cell help, it is now established that mouse EF B cell responses can undergo affinity maturation and generate both memory and long-lived plasma cells even under T cell independent conditions 12,13 . Driven by IFN-γ and IL-21, Toll-like…”

mentioning

confidence: 99%

Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19

et al. 2020

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A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling.

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“…Repertoire differences between MBM and MBG are well documented in circulating B-cell subsets (Bagnara et al, 2015;Wu et al, 2010) , but to the best of our knowledge, the present work is the first time that IgM and IgG repertoires have been compared in antibodies specific for the same antigen. Antibody responses dominated by IgM are characteristic of T-independent antigens (Allman et al, 2019) , and indeed, the humoral response to mouse polyomavirus is T-independent (Guay et al, 2009;Szomolanyi-Tsuda & Welsh, 1996) . Polyomavirus capsids are rigid structures presenting multiple copies of the same epitope in an ordered array, which is similar to the structural properties of the TI-2 antigens.…”

Section: Discussionmentioning

confidence: 99%

The humoral response to BK polyomavirus in kidney transplant recipients is dominated by IgM antibodies that use a distinct repertoire compared to IgG against the same antigen

Ngoc-Khanh

Laetitia

Marie-Claire

et al. 2021

Preprint

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The BK polyomavirus (BKPyV) persists asymptomatically in the kidney and active replication is only seen in immunosuppressed individuals, such as kidney transplant (KTx) recipients, in whom BKPyV reactivation can cause significant morbidity. KTx recipients with BKPyV reactivation mount a robust humoral response, but this often fails to clear the virus. In order to characterize the BKPyV-specific B-cell receptor (BCR) repertoire in KTx recipients, we used fluorescence-labeled BKPyV virus-like particles (VLPs) to sort with BKPyV-specific B-cells, then single-cell RNAseq to obtain paired heavy and light chain antibody sequences, and gene transcriptome data. The BCR repertoire was highly diverse in terms of both V-gene usage and clonotype diversity, with approximately 3% repertoire overlap between patients. The BKPyV-specific response was characterized by the presence of both memory IgG and memory IgM B-cells with extensive somatic hypermutation, which expressed distinct BCR repertoires within the same patient. The gene expression profile of IgG and IgM memory B-cells was highly similar, with only 19 genes, including CD83, CD79A and PARP1 showing significant differential expression. These results confirm that the IgM memory B-cells are a significant component of the BKPyV-specific humoral response, and show for the first time that IgG and IgM repertoires directed against the same antigen can have significant differences.

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The continuing story of T‐cell independent antibodies

Cited by 80 publications

References 79 publications

Recovery from acute SARS-CoV-2 infection and development of anamnestic immune responses in T cell-depleted rhesus macaques

Recovery from acute SARS-CoV-2 infection and development of anamnestic immune responses in T cell-depleted rhesus macaques

Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19

The humoral response to BK polyomavirus in kidney transplant recipients is dominated by IgM antibodies that use a distinct repertoire compared to IgG against the same antigen

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