Andrew Caton, Ph.D.
Professor, Wistar Institute
Address: 3601 Spruce St., Philadelphia, PA 19104
Office Phone: (215) 898-3871
Lab Phone: (215) 898-3839
Fax: (215) 898-3868
Ph.D., Cambridge University, U.K.
B.Sc., University of East Anglia, U.K.
Immune repertoire formation; CD4+ T and B cell tolerance; autoimmunity; viral immunology
Strategy for using T cell receptor transgenic mice to examine effects of the neo-self hemagglutinin on T cell repertoire formation.
In the healthy adult, the immune system generates a repertoire of B and T lymphocytes that can recognize and eliminate infecting microorganisms, and yet remain unresponsive toward the host's own cells and tissues. The goal of our research is to define the mechanisms by which self-reactive lymphocytes are regulated, and to understand how these processes fail and/or can be manipulated in disease states such as cancer and autoimmunity. Our experimental approaches center on a transgenic mouse system we have developed in which the influenza virus A/PR/8/34 hemagglutinin (PR8 HA) is a model self antigen. The HA molecule provides an extremely powerful system for analyzing the specificity of self recognition, because our previous studies have defined the location and structure of B and T cell determinants on the PR8 HA. We have also previously examined the genetic basis by which HA-specific immunoglobulin and T cell receptors (TCRs) are generated in BALB/c mice. As a result of these past studies, we are now able to examine how the HA is recognized as a well-characterized self antigen in HA-transgenic (HA Tg) using the wealth of reagents and information we have gained by studying its recognition as a foreign antigen.
To examine how variations in the expression of self proteins can affect their recognition by autoreactive T and B cells, we have generated multiple lineages of transgenic mice that the HA in different tissues and cell types (HA Tg mice). By mating these mice with transgenic mice expressing HA-specific class II-restricted TCRs, we have demonstrated that T cells with identical specificity for a self peptide can display distinct and unique mechanisms and manifestations of CD4+ T cell tolerance. In some lineages, the neo-self HA induces the formation of anergic/suppressor T cells that regulate the T cell responses to the self antigen. In other lineages, HA-specific T cells are deleted, although even when deletion is induced, cells that evade deletion can exhibit diverse functional potentials ranging from altered cytokine responses to the development of systemic autoimmunity. These findings clearly establish that heterogeneity in the pattern of self antigen expression can significantly impact how and whether autoreactive CD4+ T cells are regulated.
In our ongoing studies, we are seeking to determine how parameters such as the avidity of the TCR for the self peptide and the recognition of distinct CD4+ T cell epitopes affect the extent and mechanism(s) by which autoreactive T cells are regulated. We are also seeking to understand how autoreactive CD4+ T cells can become activated to mediate autoimmune pathology. We have been performing similar studies of HA-specific B cell repertoire formation in HA Tg mice, and have again found that there can be considerable heterogeneity in the regulation of autoreactive B cells. We have found that a B cell population that dominates primary responses to the HA in BALB/c mice is deleted from the B cell repertoire of HA Tg mice, but that precursors of memory cells evade negative selection and can be activated by virus immunization. Overall, our long-term objective is to use this well-characterized and easily manipulable experimental system to understand the mechanisms by which an effective immune repertoire is generated in healthy individuals, and to determine processes by which these mechanisms break down and/or can be manipulated in autoimmunity.
Reed, A.J., Riley, M.P., and Caton, A.J. 2000. Virus-induced maturation and activation
of autoreactive memory B cells. J. Exp. Med. 192: 1763-1774.
Riley, M.P., Shih, F.F., Jordan, M.S., Petrone, A.L., Cerasoli, D.M., Scott, P., and Caton,
A.J. 2001. CD4+ T cells that evade deletion by a self peptide display Th1-biased
differentiation. Eur. J. Immunol. 31: 311-319.
Jordan, M.S., Boesteanu, A., Reed, A.J., Petrone, A.L., Holenbeck, A.E., Lerman, M.A.,
Naji, A., and Caton, A.J. 2001. Thymic selection of CD4+ CD25+ regulatory T cells
induced by an agonist self-peptide. Nature Immunol. 2: 301-306.
Bensinger, S.J., Bandeira, A., Jordan, M.S., Caton, A.J., and Laufer, T.M. 2001. Major
histocompatibility complex class II-positive cortical epithelium mediates the selection of
CD4+25+ immunoregulatory T cells. J. Exp. Med. 194: 427-438.
Seo, S., Fields, M.L., Buckler, J.L., Reed, A.J., Mandik-Nayak, L., Nish, S.A., Noelle,
R.J., Turka, L.A., Finkelman, F.D., Caton, A.J., and Erikson, J. 2002. The impact of T
helper and T regulatory cells on the regulation of anti-double-stranded DNA B cells.
Immunity 16: 535-546.
Trani, J., Moore, D.J., Jarrett, B.P., Markmann, J.W., Lee, M.K., Singer, A., Lian, M-M., Tran, B, Caton, A.J, and Markmann, J.F. 2003. CD25+ immunoregulatory CD4 T cells mediate acquired central transplantation tolerance. J. Immunol. 170: 279-286.