News and Publications

Helper T Cell-Regulated B-Cell Immunity

Adaptive immunity aids clearance of pathogens through antigen-specific effector mechanisms and provides long-term protection against reinfection through the development of immune memory. We focus on antigen-specific B-cell immunity and seek to unravel the cellular and molecular mechanisms that regulate its development in vivo.

Functional Diversity In Naive Helper T Cells

Helper T cells are the antigen-specific regulators of B-cell responses. Our recent findings indicate a major division in naive helper T cells based on the expression of Ly6C, a glucose-6-phosphate isomerase-anchored membrane glycoprotein. Differential expression of Ly6C in the periphery is a consequence of early events in thymic selection that result in the development of different compartments of naive helper T cells that have identical specificity but distinct repertoires of T-cell receptors. Functional analysis of the separate subsets indicated that the different populations of naive helper T cells differ in the capacity to promote the development of plasma cells in vivo. Thus, preexisting functional diversity in naive helper T cells can substantially affect the development of B-cell immunity.

Antigen-Experienced Dendritic Cells

It has become increasingly clear that the innate immune system is the critical initiator of adaptive immunity to most infectious agents. Dendritic cells are the most efficient cells in this regard, specialized for antigen capture. Mature dendritic cells must express specific peptide-MHC class II complexes to regulate the responses of helper T cells in an antigen-specific, cognate manner. Using antibodies to specific peptide-MHC molecules and extensive cell-surface phenotype, we can now isolate antigen-experienced dendritic cells directly ex vivo. Using this approach, we quantified the response of dendritic cells to local immunization with protein antigen, and we now have access to purified populations of antigen-experienced dendritic cells for subsequent analysis of gene expression programs and cellular function. In these studies, we will focus on the interface between innate and adaptive immunity, to study how dendritic cells regulate antigen-specific helper T cells and how these outcomes affect the fate of antigen-specific B cells in vivo.

Antigen-Specific Development of Helper T Cells

We continue our research on the development of antigen-specific helper T cells in the response to immunization with proteins. Our recent studies on antigen-driven selection of T-cell receptors indicated that among the responsive helper T cells that dominate the response to a specific antigen, the frequency of preimmune precursors is the driving cellular attribute and not the binding kinetics of the T-cell receptor for peptide-MHC. This mechanism may be the one used by helper T cells to develop and maintain diverse function. This cellular diversity is apparent at the level of the cell-surface phenotype, with multiple discrete subsets of antigen-specific helper T cells evident in the effector and memory helper T cell compartments.

This diversity in phenotype and repertoire appears to be controlled at the level of the microenvironment, because the responses of helper T cells in the spleen and lymph nodes are qualitatively and quantitatively distinct. The precise function of helper T cells in germinal centers in either microenvironment is of particular interest. Our recent identification of a cell-surface marker associated with germinal center assortment in vivo has substantially aided this current effort.

Development of Antigen-Specific B Cells

Development of antigen-specific B-cell memory is poorly understood. Our recent findings provided genetic evidence for a linear differentiation model in the development of antigen-specific B-cell memory. We found that the progression of cellular development from memory B cells positive for B220 (the B-cell form of CD45) to B220-negative preplasma memory B cells was profoundly blocked in the absence of IL-6. This defect was overcome in the memory response to antigen, suggesting that IL-6 functions at the early stages of memory development and that its activity may be redundant in the presence of helper T cell memory. We complemented these studies with biochemical assessment of B-cell receptor signaling in naive and memory B cells. In these studies, we identified a calcineurin-dependent signaling pathway that controls rapid upregulation of the costimulatory molecules CD80 and CD86 in memory B cells that does not occur in naive B cells.

Publications

Borron, P.J., Mostaghel, E.A., Doyle, C., Walsh, E.S., McHeyzer-Williams, M.G., Wright, J.R. Pulmonary surfactant proteins A and D directly suppress CD3⁺/CD4⁺ cell function: evidence for two shared mechanisms. J. Immunol. 15:5844, 2002.

McHeyzer-Williams, L., Malherbe, L., Eisenbraun, M., Driver, D., McHeyzer-Williams, M. Development of antigen-specific helper T cell responses in vivo: antigen-specific Th cell subsets. Adv. Exp. Med. Biol. 512:11, 2002.

McHeyzer-Williams, M., McHeyzer-Williams, L., Panus, J.F., Pogue-Caley, R., Bikah, G., Driver, D., Eisenbraun, M. Helper T-cell-regulated B-cell immunity. Microbes Infect. 5:205, 2003.

McHeyzer-Williams, M.G. B cells as effectors. Curr. Opin. Immunol. 15:354, 2003.

McHeyzer-Williams, M.G. B-cell signaling and activation. In: Fundamental Immunology, 5th ed. Paul, W.E. (Ed.). Lippincott Williams & Wilkins, Baltimore, in press.