News and Publications

Integration of Innate and Adaptive Immunity

D. Lo, C. Reilly, N. Aftahi, H. Neal, A. Nguyen, A. Vallstedt, M. Crowley, L. DiMolfetto, L. Li, M. Pauza, A. Wu

GENETICS OF CD4 T-CELL EFFECTOR FUNCTION AND AUTOIMMUNITY

The susceptibility to autoimmune diseases such as diabetes is a multigenic phenomenon due to contributions from several polymorphic, but otherwise normal, genetic loci. Our interest is in determining which genetic components lead to susceptibility to autoimmune disease, with specific attention to the genes that regulate the function of T lymphocytes.

We have been using a transgenic mouse model in which a well-defined antigen, influenza hemagglutinin, is expressed in pancreatic islet beta cells and a hemagglutinin-specific receptor is expressed on CD4 T cells. When mice with these transgenes were backcrossed to different mouse strains (B10.D2 and BALB/c), we found striking differences in the development of spontaneous autoimmune disease that appear to be related to the expression of IFN- and IL-4 in CD4 T cells. We are analyzing genetic backcrosses to map the gene or genes that influence this cytokine regulation. Several loci have been detected that correlate with effects on T-cell function, including proliferation of CD4 T cells, the CD4/CD8 ratio, and the production of cytokines.

REGULATION OF THE DEVELOPMENT AND FUNCTION OF DENDRITIC CELLS

Mice deficient in relB (relB knockout mice) have defects in the production of mature lymphoid dendritic cells, although stem cells from these mice generate cells with dendritic cell--like properties when cultured in the presence of granulocyte-macrophage colony-stimulating factor. Thus, although cells from relB knockout can commit to the dendritic cell lineage, they cannot develop into mature lymphoid dendritic cells. Consistent with this hypothesis, relB knockout mice lack organized lymphoid tissues such as lymph nodes and Peyer's patches, and the cellular immune responses of the animals are impaired. Ongoing studies focus on the development and lineage relationships of subsets of dendritic cells and the role of transcription factors such as relB and Ikaros.

INNATE AND ADAPTIVE IMMUNITY IN THE REGULATION OF INFLAMMATION

Previously, we noted that the pancreatic islets in animals with autoimmune diabetes have a unique pattern of lymphocyte infiltration that resembles that of organized secondary lymphoid tissue. Because it has been proposed that such infiltrates are driven by antigen-specific type 1 helper T cells rather than by regulatory type 2 helper T cells, we have been studying the mechanisms that regulate antigen-dependent tissue inflammation.

An important finding was that tissue parenchymal cells, including fibroblasts, are induced by "danger" signals to produce various patterns of chemotactic cytokines (chemokines) (Fig. 1) and that the transient expression of these cytokines is suppressed by the induction of relB. We also found that cells respond to different stimuli with specific patterns of chemokines. For example, endotoxin appears to induce chemokines more specific for the recruitment of neutrophils, whereas IFN- or TNF- induces chemokines more specific for mononuclear cells. Similarly, cytokines produced by type 1 and type 2 helper T cells also induce different patterns of chemokines; thus, cytokines associated with type 2 helper T cells induce expression of the eosinophil-specific chemokine eotaxin in lung epithelial cells. On the basis of these observations, we developed the working hypothesis that the tissue-specific regulation of inducible chemokine expression is a critical factor in the regulation of tissue inflammation. Ongoing studies are aimed at determining whether this phenomenon can explain the unique patterns of antigen-dependent inflammation in diverse situations such as lung allergic inflammation and pancreatic islet autoimmunity.

PUBLICATIONS

Carson, M.J., Reilly, C.R., Sutcliffe, J.G., Lo, D. Mature microglia resemble immature antigen presenting cells. Glia 22:72, 1998.

Chen, S., Bacon, K.B., Li, L., Garcia, G., Xia, Y., Lo, D., Siani, M.A., Feng, L. In vivo inhibition of CC and CX3C chemokine-induced leukocyte infiltration and attenuation of glomerulonephritis in WKY rats by vMIP-II. J. Exp. Med., in press.

Crowley, M., Lo, D. Targeted gene knockouts: Insights into dendritic cell biology. In: Dendritic Cells: Biology and Clinical Application. Lotze, M.T., Thomson, A.W. (Eds.). Academic Press, San Diego, in press.

DiMolfetto, L., Neal, H.A., Wu, A., Reilly, C., Lo, D. The density of the class II MHC T cell receptor ligand influences IFN-/IL-4 ratios in immune responses in vivo. Cell. Immunol. 183:70, 1998.

DiMolfetto, L., Reilly, C., Wei, Q., Lo, D. Dendritic-like cells from relB mutant mice. Adv. Exp. Med. Biol. 417:47, 1997.

Gerloni, M., Lo, D., Ballou, W.R., Zanetti, M. Immunologic memory after somatic transgene immunization is positively affected by priming with GM-CSF and does not require bone-marrow derived dendritic cells. Eur. J. Immunol., in press.

Gerloni, M., Lo, D., Zanetti, M. DNA immunization in relB-deficient mice discloses a role for dendritic cells in IgM*IgG1 switch in vivo. Eur. J. Immunol. 28:516, 1998.

Laufer, T., Glimcher, L., Lo, D. Using thymus anatomy to dissect T cell repertoire selection. Semin. Immunol., in press.

Li, L., Xia, Y., Nguyen, A., Feng, L., Lo, D. Th2-induced eotaxin expression and eosinophilia coexist with Th1 responses at the effector stage of lung inflammation. J. Immunol., in press.

Lo, D. Immunological tolerance: Is self/non-self discrimination required for preventing autoimmunity? In: Immunologically Mediated Endocrine Diseases. Martini, L., et al. (Eds.). Lippincott-Raven, Philadelphia, in press.

Lo, D., Aftahi, N., Reilly, C.R., Neal, H., Sim, B.-C., Gascoigne, N.R.J., Kono, D., Wu, A., Schulman, S., Scott, B. Mapping genes regulating lymphocyte function: Correlations with autoimmunity? In: Current Directions in Autoimmunity. Theofilopoulos, A.N. (Ed.). Karger, New York, in press.

Sim, B., Aftahi, N., Reilly, C.R., Bogen, B., Schwartz, R.H., Gascoigne, N.R., Lo, D. Thymic skewing of the CD4/CD8 ratio maps with the T cell receptor -chain locus. Curr. Biol. 8:701, 1998.

Sim, B.-C., Lo, D., Gascoigne, N.R.J. Preferential expression of TCR V regions in CD4/CD8 subsets: Class discrimination or co-receptor recognition? Immunol. Today 19:276, 1998.

Tanabe, S., Lu, Z., Luo, Y., Quackenbush, E.J., Berman, M.A., Collins-Racie, L.A., Mi, S., Reilly, C., Lo, D., Jacobs, K.A., Dorf, M.E. Identification of a new mouse ß-chemokine, TCA-4, with activity on T lymphocytes and mesangial cells. J. Immunol. 159:5671, 1997.

Wu, A., Schulman, S.J., Marconi, L.A., Reilly, C., Scott, B., Lo, D. Protection against diabetes by MHC heterozygosity and reversal by cyclophosphamide. Cell. Immunol., in press.