The Wesemann laboratory uses mouse genetics, human studies, cellular biology, single cell transcriptomics, and computation to elucidate underlying features and elasticity of antibody recognition capacity. We study the dynamic regulation, functional significance, and evolutionary implications/origins of the anticipatory naïve antibody repertoire and its somatically evolving counterpart in germinal centers. Findings from these projects have paradigm-shifting potential for fundamental immunology and are relevant to infectious disease, vaccinology, allergy, and autoimmunity.
Principles Shaping Antibody Repertoires
B cell antibody (i.e. immunoglobulin (Ig)) repertoire composition shapes immune responses. The generation of Ig diversity begins with Ig variable (V) region exon assembly from gene segments, random inter-segment junction sequence diversity, and combinations of Ig heavy and light chain. This generates vast preemptive sequence freedom in early developing B lineage cell Ig genes that can anticipate a great diversity of threats. This freedom is met with large restrictions that ultimately define the initial naïve Ig repertoire. Activation-induced somatic hypermutation (SHM), which further diversifies Ig V regions, is also met with strong selection that shapes Ig affinity maturation. While individual repertoire features, such as affinity for self and competition for foreign antigen, are known to drive selection, the selection filters themselves may be subject to regulation. We are carrying out investigations testing the hypothesis that tolerance filter stringency is flexible to enable demand-driven regulation to dynamically balance antigen recognition capacities and associated autoimmune risks according to host needs for both primary naïve and activation-dependent Ig repertoires.
Germinal Center B Cell Clonal Selection and Somatic Antibody Evolution
Two Ig diversification mechanisms collaborate to provide protective humoral immunity. Combinatorial assembly of IgH and IgL V region exons from gene segments generates preimmune Ig repertoires, expressed as B cell receptors (BCRs). Secondary diversification occurs when Ig V regions undergo SHM and affinity-based selection toward antigen in activated germinal center (GC) B cells. Secondary diversification is thought to only ripen the antigen-binding affinity of Igs that already exist (i.e., cognate Igs) because of chance generation during preimmune Ig diversification. However, some high affinity antibodies may have evolved from BCRs that may have had no initial recognition of antigen. We recently discovered that intrinsic GC B cell flexibility allows for somatic, noncognate B cell evolution, permitting de novo antigen recognition and subsequent antibody affinity maturation without initial preimmune BCR engagement. We are currently developing models to understand this process in physiologically competitive environments as well as its relevance to the initial activation of unmutated germline ancestors of protective antibodies.
Origins of Real-Time Somatic Evolution
Jawless vertebrate (agnathan) immune systems are supported by lymphocyte subsets that express variable receptors (VLRs) analogous to jawed vertebrate (gnathostome) BCRs. In contrast to BCRs, which are made of Ig domains, VLRs are made of leucine rich repeat (LRR) domain-containing gene segments. Three types of VLRs have been identified, termed VLRA, VLRB, and VLRC—and they are expressed on agnathan lymphocytes that share gene expression modules with abT cells, B cells, and gdT cells, respectively. Despite sharing genes capable of somatic gene mutation, agnathans do not appear to have developed a somatic mutation and affinity maturation system as gnathostome B cell-expressed Igs have. We are carrying out computational and wet lab investigations to compare the gnathostome and agnathan systems to identify fundamental features that enable somatic receptor evolution.
Lymphocyte Antigen Receptor and Cell Fate
IgH isotypes (e.g., IgM, IgG, and IgE) are generated as secreted/soluble antibodies (sIg) or as membrane-bound (mIg) B cell receptors (BCRs) through alternative RNA splicing. IgH isotype dictates soluble antibody function, but how mIg isotype influences B cell behavior is not well defined. We recently found that the IgH locus produces transcripts that generate IgM, IgG1, and IgE in an alternative splice form bias hierarchy, regardless of cell stage. We are carrying out additional work to understand how BCR expression and IgH isotype influence B lineage cell fate function.
We have ongoing human studies recruiting human participants to elucidate the role of antibodies and lymphocyte dynamics in human health and disease, including autoimmunity, immune deficiency, and allergy.
Div. of Rheumatology, Immunology and Allergy
NRB 77 Avenue Louis Pasteur Room 431D
Boston, MA 02115