Biomedical subjects
Publications and source records attributed to Louise J McHeyzer-Williams.
How B cells discriminate antigen-receptor-mediated signals in development and navigate critical checkpoints in adaptive immune responses remains poorly resolved. In this issue of Immunity, conditionally ablate the main regulatory subunit of the calcineurin phosphatase complex in B cells to reveal both positive and negative influences on the development of antibody responses and B cell memory.
We consider four sequential phases in the evolution and consolidation of high affinity B-cell memory as it is regulated in a cognate manner by antigen-specific T-helper (Th) cells. Sequential developmental checkpoints control cell fate in each phase of the pathway in ways that still remain poorly understood. The cellular composition and molecular attributes of each checkpoint are of great interest, but they may vary substantially depending on the nature of the immune stimulus. How this stimulus cascades through the innate and then the adaptive immune responses defines initial effector mechanisms in both Th and B-cell compartments. The germinal center reaction controls memory B-cell development with roles for antigen presentation and cognate Th cell regulation in the establishment of the memory B-cell compartment. Antigen re-challenge rapidly promotes effector responses from the memory compartments of both Th and B cells. Importantly, re-challenge also expands and consolidates immune memory at the serological and cellular levels. We review recent advances in our understanding of memory B-cell evolution with emphasis on the regulatory checkpoints that control lymphocyte fate at each developmental juncture.
Helper T (Th) cell-regulated B cell immunity progresses in an ordered cascade of cellular development that culminates in the production of antigen-specific memory B cells. The recognition of peptide MHC class II complexes on activated antigen-presenting cells is critical for effective Th cell selection, clonal expansion, and effector Th cell function development (Phase I). Cognate effector Th cell-B cell interactions then promote the development of either short-lived plasma cells (PCs) or germinal centers (GCs) (Phase II). These GCs expand, diversify, and select high-affinity variants of antigen-specific B cells for entry into the long-lived memory B cell compartment (Phase III). Upon antigen rechallenge, memory B cells rapidly expand and differentiate into PCs under the cognate control of memory Th cells (Phase IV). We review the cellular and molecular regulators of this dynamic process with emphasis on the multiple memory B cell fates that develop in vivo.
Differential Ly6C expression identifies a major phenotypic division in CD44loCD62LhiCD4+ Th cells. Using two separate models of single subset adoptive transfer, we demonstrate the unique capacity of Ly6Chi Th cells to promote antigen-specific plasma cell production in vivo. In contrast, both compartments support germinal center formation and proliferate to equivalent levels upon TCR triggering in vivo and in vitro. Developmentally, CD4+CD8- thymocytes leave the thymus expressing low levels of Ly6C; 3 days later approximately 50% stably upregulate Ly6C without cell division or TCR engagement in the periphery. Interestingly, antigen-specific Th cell clonotypes unevenly assort into these peripheral compartments, creating separate TCR repertoires that underpin peripheral functional diversity. Taken together, these data reveal a developmentally distinct Ly6Chi naive Th cell compartment subspecialized to regulate plasma cell production in vivo.
Helper T-cell-regulated B-cell memory develops in response to initial antigen priming as a cellular product of the germinal center (GC) reaction. On antigen recall, memory response precursors expand rapidly with exaggerated differentiation into plasma cells to produce the high-titer, high-affinity antibody(Ab) that typifies the memory B-cell response in vivo. We have devised a high-resolution flow cytometric strategy to quantify the emergence and maintenance of antigen-specific memory B cells directly ex vivo. Extended cell surface phenotype establishes a level of cellular diversity not previously appreciated for the memory B-cell compartment. Using an "exclusion transfer" strategy, we ascertain the capacity of two distinct memory B-cell populations to transfer antigen-specific memory into naive adoptive hosts. Finally, we sequence expressed messenger ribonucleic acid (mRNA) from single cells within the population to estimate the level of somatic hypermutation as the best molecular indicator of B-cell memory. In this chapter, we describe the methods used in each of these four sections that serve to provide high-resolution quantification of antigen-specific B-cell memory responses directly ex vivo.
Blimp-1 is a transcriptional repressor able to drive the terminal differentiation of B cells into Ig-secreting plasma cells. We have created mice with a B cell-specific deletion of prdm1, the gene encoding Blimp-1. B cell development and the number of B cells responding to antigen appear to be normal in these mice. However, in response to either TD or TI antigen, serum Ig, short-lived plasma cells, post-GC plasma cells, and plasma cells in a memory response are virtually absent, demonstrating that Blimp-1 is required for plasmacytic differentiation and Ig secretion. In the absence of Blimp-1, CD79b(+)B220(-) pre-plasma memory B cell development is also defective, providing evidence that this subset is an intermediate in plasma cell development. B cells lacking Blimp-1 cannot secrete Ig or induce muS mRNA when stimulated ex vivo. Furthermore, although prdm1-/- B cells fail to induce XBP-1, XBP-1 cannot rescue plasmacytic differentiation without Blimp-1.