Scientific Report 2005

Immunology

Helper T Cell–Regulated B-Cell Immunity

M.G. McHeyzer-Williams, L.J. McHeyzer-Williams, L.P. Malherbe, A.P. O’Connor

Production of high-affinity antibodies is considered the most effective long-term protection against reinfection by pathogens. Hence, vaccines need to promote strong, long-lasting memory in the antigen-specific B-cell compartment to ensure persistent adaptive immunity in vivo. We seek to understand the rules that govern the helper T cell–regulated development of the antigen-specific B-cell memory. We focus our efforts on well-characterized murine models of immunity to protein antigens.

Antigen-Experienced Dendritic Cells

Dendritic cells initiate most aspects of adaptive immunity. Primarily, their capacity for antigen uptake, antigen processing, and presentation of foreign peptides recruits antigen-specific helper T cells. Using antibodies to complexes consisting of specific peptides and MHC class II molecules, we can identify antigen-experienced dendritic cells in the secondary lymphoid organs draining sites of protein vaccination. The extent and dynamics of this cellular response vary with adjuvant and dose of antigen, providing an important quantitative index of immunogenicity in vivo. We propose that these differences critically affect the fate and the function of naive antigen-specific helper T cells recruited into the adaptive phase of the immune response. This approach provides new and objective ways to evaluate the impact of vaccination regimens on the quality of adaptive immunity in vivo.

Development of Antigen-Specific Helper T Cells

The specificity of clones that respond to foreign antigens is the earliest defining attribute of adaptive immunity. The rules that underpin this selection process for helper T cells have been difficult to assess experimentally. Using an adoptive transfer model and binding of T cells to complexes consisting of peptide and MHC class II molecules, we detected and quantified the selective loss of antigen-specific clonotypes that express lower affinity antigen receptors. This affinity-threshold selection is followed by the unbiased propagation of preferred clonotypes regardless of binding half-lives or affinity. We propose that this unique selection mechanism establishes and maintains functional heterogeneity among antigen-experienced helper T cells in vivo.

Development of Antigen-Specific B Cells

The cellular organization of B-cell memory affects the quality and quantity of the immune response to antigen rechallenge. We are studying the complex development and cellular organization of antigen-specific memory B cells. Using antigen binding, cell-surface phenotype, single-cell analysis of the diversity of the antigen receptor repertoire, and gene expression analysis directly ex vivo, we are determining a comprehensive and unique view of subsets of memory B cells after initial antigen priming and after challenge with the priming antigen later on in vivo. We propose a linear progression of development from typical memory phenotype B cells that exit the germinal center reaction to a compartment of distinct and persistent preplasma memory B cells that appear to be the immediate cellular precursors of high-affinity plasma cells.

Publications

Malherbe, L., Hausl, C., Teyton, L., McHeyzer-Williams, M.G. Clonal selection of helper T cells is determined by an affinity threshold with no further skewing of TCR binding properties. Immunity 21:669, 2004.

McHeyzer-Williams, L.J., Malherbe, L.P., McHeyzer-Williams, M.G. Helper T cell regulated B cell immunity. Curr. Top. Microbiol. Immunol., in press.

McHeyzer-Williams, L.J., McHeyzer-Williams, M.G. Analysis of antigen-specific
B cell memory directly ex vivo. Methods Mol. Biol. 271:173, 2004.

McHeyzer-Williams, L.J., McHeyzer-Williams, M.G. Antigen-specific memory B cell development. Annu. Rev. Immunol. 23:487, 2005.

McHeyzer-Williams, M.G. Memory B cell development. In: The Autoimmune Diseases, 4th ed. Rose, N.R., Mackay, I.R. (Eds.). Elsevier, St. Louis, in press.