Biology subjects

Silva Santos, G. S.

Publications and source records attributed to Silva Santos, G. S..

4 recordsLinked to original sources

bioRxiv2026

Biophysical properties of IgD determine thresholds for self-tolerance and selection into germinal centers

Immunoglobulin D (IgD) is among the most conserved antibody isotypes, found in virtually all jawed vertebrates1. Unlike other isotypes, IgD contains an unusually long hinge region of up to 160 amino acids that connects the constant and variable regions. Its expression pattern is also conserved; IgD is co-expressed with IgM on transitional and mature naive B cells. However, the function of IgD has remained enigmatic since its discovery in 19652,3. Here we present and test a biophysical model positing that IgD increases the entropic cost of bivalent antigen binding. Single-molecule measurements revealed that the antigen-binding arms of IgD are substantially more dynamic than those of IgM, suggesting that cell surface IgD would be energetically penalized in bivalent antigen binding. Consistent with the model and biophysical data, we find that the long hinge compromises antigen capture by IgD B cell receptors (BCRs) compared to IgM BCRs. To determine how the difference in antigen binding impacts immunity, we produced mice that express only IgM and IgD, exclusively IgM or IgD, or IgD with a truncated hinge region. The data indicate that the increased entropic cost of antigen binding imposed by the IgD hinge attenuates negative selection by self-antigen while increasing the affinity-based threshold for positive selection into the germinal center (GC). Together the results indicate that IgD functions physiologically to desensitize B cells to antigen, thereby expanding the B cell repertoire while optimizing affinity-based selection into the GC.

immunology↗

bioRxiv2026

Fc receptor dependent and independent mechanisms of antibody-mediatedenhancement of immune responses

Immune memory responses are rapid and qualitatively distinct from primary responses. They typically develop in the presence of antigen-experienced memory T and B cells and pre-existing antibodies. Although the contribution of T and B cells to recall responses is well defined, the contribution of antibody "memory" and the mechanisms by which pre-existing antibodies modulate the development of germinal center and plasma cell responses is not precisely understood. Here we report on mechanisms that mediate antibody enhancement of germinal center (GC) and plasmablast (PB) compartments, and the parallel process by which they change the affinity threshold for B cell recruitment into immune responses. The data indicate that antibody-mediated enhancement of GC and PB responses is Fc gamma receptor (Fc{gamma}R) dependent and largely complement receptor 1 and 2 (CR1/2) independent. In contrast, the reduction in the affinity threshold for GC entry is independent of both Fc{gamma}Rs and CR1/2. SummaryCipolla et al. show that antibody can modulate immune responses via both Fc gamma receptor dependent and independent mechanisms. These mechanisms influence both the magnitude and composition of the germinal center response.

immunology↗

bioRxiv2025

Clonal Expansion and Diversification of Germinal Center and Memory B Cell Responses to Booster Immunization in Primates

Effective vaccines elicit B cell clonal expansion in germinal centers (GCs) that produce memory B cells and antibody secreting plasma cells. Studies in mice indicate that, whereas the plasma cell compartment is enriched for cells producing high affinity antibodies, the memory pool is more diverse and contains only a relatively small proportion of higher affinity cells. Upon boosting, murine memory B cells producing high affinity antibodies tend to develop into plasma cells but few if any re-enter GCs. However, mice live for only a few weeks in nature, and in keeping with the rather limited requirement for immune memory, this compartment comprises only 1-2% of all B cells. In contrast, memory accounts for nearly 50% of all B cells in primates. Here we examine memory and GC B cell responses in rhesus macaques immunized and boosted ipsilaterally or contralaterally with an mRNA vaccine encoding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein. The neutralizing activity of antibodies cloned from the memory compartment, and the size of the compartment, was independent of the site of boosting. Moreover, in primates, memory B cells enter and undergo iterative expansion in newly developing GCs when boosting is at a site distal to the site of priming. Thus, in primates, high affinity memory B cells constitute a reservoir that actively participates in further development of immunity irrespective of the anatomical site of vaccine boosting. Highlights- Clonal overlap between primate memory and germinal center B cell compartments following booster immunization. - Neutralization activity of the memory and germinal center compartments are independent of the boost site. - Relationship between site of booster immunization (ipsilateral versus contralateral) and development of memory and germinal center (GC) responses in primates

immunology↗

bioRxiv2024

Transcription of HIV-1 at sites of intact latent provirus integration

HIV-1 anti-retroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 100-10,000X less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir thereby influencing cytopathic effects and proviral immune evasion.

immunology↗