News and Publications

Regulation of T-Cell Memory

L.M. Bradley, J. Harbertson, J.J. Bacwaden, L. Schioetz, P.-J. Linton,* S.R. Watson**

* Sidney Kimmel Cancer Center, La Jolla, CA
** EOS Biosystems, South San Francisco, CA

Immunologic memory refers to the capacity of an organism to mediate rapid and effective responses to previously encountered antigens. Memory is in large part regulated by CD4 cells. However, little is known about the mechanisms that regulate memory in this population of cells. Our studies focus on defining the roles of antigen, antigen-presenting cells, and cytokines in the development of subsets of memory CD4 cells. The subsets, which are distinguished by the cytokines they secrete, include type 1 (IFN- and lymphotoxin) and type 2 (IL-4, IL-5, IL-6, IL-10, and IL-13) helper T cells and mixtures of both types.

Although dendritic cells are essential antigen-presenting cells for initiation of CD4 responses, we found that B cells have a critical function as antigen-presenting cells for optimal development of memory in the CD4 population and in eliciting memory effector responses. Memory CD4 cells can regulate their own development into type 1 and type 2 helper T cells through autocrine use of IFN- and IL-4, respectively. Moreover, cytokines produced by memory cells participate in feedback loops that promote activation and induction of the costimulatory activity of antigen-presenting cells.

Memory T cells provide long-lasting immunity in part by immunologic surveillance, which is achieved by their recirculation through lymphoid and possibly nonlymphoid tissue. Both antigen and the route of immunization may influence development of memory CD4 subsets that preferentially recirculate through lymphoid tissue draining the site or sites of initial exposure to antigen. We are using transgenic mouse models to study how cytokines, chemokines, and antigen regulate infiltration of CD4 subsets into sites of inflammation such as the pancreas in autoimmune diabetes, lung allografts, and inflamed skin.

Results in the diabetes model indicate that although only type 1 helper T cells cause disease, both type 1 and type 2 cells induce multiple adhesion molecules on vascular endothelium of the pancreas and infiltrate islets. However, type 1 cells differ from type 2 cells by synthesis of several chemokines and by expression of chemokine receptors. Our studies reveal the potential for autocrine use of chemokines and cytokines in situ that results in distinctive inflammatory infiltrates.

Differences in expression of adhesion molecules are thought to underlie distinct recirculation pathways of memory and naive CD4 cells. Our studies in transgenic models and in normal mice indicate that in contrast to naive cells, most memory cells lack L-selectin, the lymph node homing receptor, and do not home to lymphoid tissues where entry is controlled through high endothelial venules. Memory CD4 cells predominantly localize in the spleen, where they are ideally situated to encounter systemic antigens. Our studies indicate that once activated, CD4 memory cells can be recruited into lymph nodes draining sites of antigen injection.

PUBLICATIONS

Balasa, B., Deng, C., Lee, J., Bradley, L.M., Dalton, D.K., Christadoss, P., Sarvetnick, N. IFN- is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice. J. Exp. Med. 186:385, 1997.

Bradley, L.M., Watson, S.R. Blockade of both L-selectin and ₄ integrins abrogates naive CD4 cell trafficking and responses in gut-associated lymphoid organs. Int. Immunol., in press.

Dutton, R.W., Bradley, L.M., Swain, S.L. T-cell memory. Adv. Immunol. 16:201, 1998.

Horwitz, M.S., Bradley, L.M., Harbertson, J., Krahl, T., Lee, J., Sarvetnick, N. Coxsackie virus-induced diabetes: Initiation by bystander damage and not molecular mimicry. Nature Med., in press.

Mueller, R., Bradley, L.M., Krahl, T., Sarvetnick, N. Mechanisms underlying counter regulation of autoimmune diabetes by IL-4. Immunity 7:411, 1997.

Watson, S.R., Bradley, L.M. The recirculation of naive and memory lymphocytes. Cell Adhes. Commun., in press.