ANTIGEN-SPECIFIC HELPER T CELL IMMUNITY
Pre-Immune Diversity in the Th Cell Compartment. We have recently uncovered a novel phenotypic division in the naive Th cell compartment based on the differential expression of Ly6C. While we do not understand the function of this GPI-linked surface glycoprotein, its expression in the naïve Th cell compartment appears to be programmed in the thymus and divides the pre-immune repertoire specific for individual pMHCII complexes. Interestingly, the Ly6Chi Th cells promote 10-fold greater numbers of antibody-secreting cells than their Ly6Clo counterparts. We are now focusing on the divergent developmental programs expressed by these cells and how this changes after antigen exposure.
| Clonal Selection in the Th Cell Compartment. We have recently described an affinity threshold model for selection of antigen-specific Th cells into the response to protein antigen. What’s unique about this model is how clonal diversity is achieved and maintained through the progressive loss of lower affinity cells rather than the preferential expansion of the high affinity clonotypes. We have evidence to suggest that this is not due to inter-clonal competition, but is a more intrinsic threshold with a “set point” for selection. Hence, to manipulate antigen-specific clonal diversity one must alter this affinity threshold. We are currently examining multiple variables of vaccination to define these rules. |
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What is the Nature of T Cell Help In vivo. Helper T cells are master regulators of antigen-specific B cell fate in vivo. Antigen-specific Th cells exert a spectrum of effector functions at first contact with antigen-primed B cells (checkpoint II), in the germinal center reaction controlling memory B cell development (Checkpoint III) and during the response to antigen re-challenge (Checkpoint IV). A precise understanding of these functions, their distribution across the responsive Th cell compartment and how they influence B cell functions such as isotype switch, affinity maturation, memory B cell and plasma cell development remain poorly resolved.
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| These studies aim to define the rules that govern Th cell clonal selection in vivo. These fundamental processes serve determine the fate and perhaps shape the effector function of antigen-specific Th cells. Importantly, the spectrum of effector functions subsequently drives the quality and quantity of B cell responses to protein antigen that ultimately determine the efficacy of long term immune protection. Hence, if we can unravel these rules with molecular resolution and learn to induce particular desired functions, we will understand how to design effective the protein vaccines. |
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KEY PUBLICATIONS
• McHeyzer-Williams, M.G. & Davis M.M. (1995) Antigen-specific helper T-cell development in vivo. Science. 268:106. PubMed Abstract
• Altman, J.D., Moss, P.A.H., Goulder, P.J.R., Barouch, D.H., McHeyzer-Williams, M.G., Bell, J.I., McMichael, A.J., Davis, M.M. (1996) Phenotypic analysis of antigen-specific T Lymphocytes. Science. 274:94-96.
PubMed Abstract
• McHeyzer-Williams, L.J., Fanelli Panus, J., Mikszta, J.A., McHeyzer-Williams, M.G. (1999) Evolution of antigen-specific T cell receptors in vivo: Pre-immune and antigen-driven selection of preferred CDR3 motifs. J. Exp. Med. 189 (11):1823-1837. PubMed Abstract
• Bikah, G.*, Pogue-Caley, R.R.*, McHeyzer-Williams, L.J. & McHeyzer-Williams, M.G. (2000) Regulating T helper cell immunity through antigen responsiveness and calcium entry. Nature Immunology 1(5):402-412. PubMed Abstract
• McHeyzer-Williams, L.J. and McHeyzer-Williams, M.G. Developmentally-distinct Th cells control plasma cell production in vivo. (2004) Immunity 20:231-242 PubMed Abstract
• Malherbe L, Hausl C, Teyton L, McHeyzer-Williams MG. Clonal selection of helper T cells is determined by an affinity threshold with no further skewing of TCR binding properties. (2004) Immunity 21(5):669-79. PubMed Abstract
• Fazilleau, N.R. McHeyzer-Williams, L.J. and McHeyzer-Williams, M.G. (2007) Local development of effector and memory T helper cells. Curr. Opin. Immunol. 19 (3) 259-267 PubMed Abstract
• Fazilleau, N.R., Eisenbraun, M.D., Malherbe, L.P., Ebright, J.N., McHeyzer-Williams, L.J. and McHeyzer-Williams, M.G. (2007) Lymphoid reservoirs of antigen-specific memory T helper cells. Nature Immunology 8:753-761 PubMed Abstract
| RESEARCH AREA |
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1. Antigen-experienced Dendritic Cells more |
| 2. Antigen-specific Helper T Cell Immunity more |
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| 4. Antigen-specific B Cell Immunity more |
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