The Role of MHC-Restricted Antigen Presentation in the Immune Response Against Invading Microbial Pathogens and Tumors

Paula Wolf Bryant
Assistant Professor
Ph.D. – Baylor College of Medicine, 1988-1993
Postdoctoral fellowship – Harvard Medical School, 1993-2000

The role of MHC-restricted antigen presentation in the immune response against invading microbial pathogens and tumors.

The focus of research in my laboratory is the role of MHC-restricted antigen presentation in the immune response against invading microbial pathogens and tumors. To eliminate infected or transformed cells, the immune system must be capable of specifically recognizing antigen. Antigen-specific receptors on T lymphocytes recognize antigen only after it has been processed into small fragments or peptides, and presented on the cell surface bound in the peptide-binding cleft of major histocompatibility complex (MHC) class I and class II molecules. MHC class II molecules acquire peptide in the enodcytic pathway, and present their cargo to CD4+ T helper cells.

My research thus far has examined the machinery required to load class II molecules with antigenic peptides in healthycells of the mouse. Shortly after synthesis in the ER, MHC class II ab-dimers interact with a third glycoprotein, the invariant chain (Ii). Sorting signals in the cytoplasmic tail of Ii target class II molecules to their site of peptide binding in the endocytic pathway. As class II-Ii complexes traverse the endocytic route Ii is sequentially degraded by the combined action of cysteine- and aspartyl-proteases. Upon completion, a small fragment of Ii, CLIP, remains bound in the peptide-binding groove of class II. The final cleavage of Ii into CLIP is performed by the cysteine proteases Cathepsin S (Cat S) in B cells, dendritic cells macrophages, and Cathepsin L (Cat L) in Thymic Epithelial Cells. To complete peptide binding, most class II alleles require interaction with yet another accessory molecule, the nonclassical class II-dimer, DM. Interaction of DM with class II facilitates exchange of CLIP for antigenic peptides.

The requirements for DM and Cat S/L in class II peptide loading were defined by examining mice in which the genes encoding these accessory molecules were ‘knocked out’. These studies only examined antigen presentation in the uninfected host. Little is known about the role of class II-restricted antigen presentation in eliminating invading pathogens or tumors, and in resolution of disease, which is the current focus of my laboratory. Pathogens have developed means to escape immune recognition and destruction. How do microbes (i.e., mycobacterium) modify or abrogate the antigen presentation pathways of the host to avoid immune recognition and attack? Likewise, T cell tolerance is emerging as one of the leading mechanisms by which tumor cells evade immune recognition. Reactivity’s of CD4+ T cells that are restricted by MHC class II molecules have been documented against melanomas, lymphomas, colon cancers, and breast cancers. What is the antigen processing machinery used by tumor cells to process and present melanoma-associated antigens via class II molecules to CD4+ T cells? How does class II conformation influence acquisition and presentation bacterial-derived or tumor-derived antigens? What are the components of class II-restricted antigen presentation used by the host to elicit a T cell-mediated immune response against microbes, and against tumors? These questions are currently being addressed in my laboratory by using the various antigen presentation-deficient mice as infectious disease and tumor progression models.

Recent Publications

Wolf Bryant, P., Feibeger, E., Lennon-Duménil, A -M. Driessen, C., and H. L. Ploegh. (2001). Peptide loading of H-2-I-Ab molecules in the absence of Cat S is strictly DM-dependent. Submitted.

Lennon-Duménil, A -M., Bryant, R. A. R., Bikoff, E. R., Ploegh, H. L., and P. Wolf Bryant. (2001). The p41 Isoform of Invariant Chain is a Chaperone for Cathepsin L. EMBO J. in press.

Hsu, P. -N., Wolf Bryant, P., Sutkowski, N., McLellan, B., Ploegh, H. L., and B. T. Huber. (2001). Association of MMTV superantigen with MHC class II during biosynthesis. J. Immunol. 166: 3309-14.

Sant, A. J., Beeson, C., McFarland, H. F., Cao, B., Ceman, S., Bryant, P. W., and S. Wu. (1999). Individual hydrogen bonds play a critical role in MHC class II:peptide interactions: implications for the dynamic aspects of class II trafficking and DM-mediated peptide exchange. Immunol. Reviews. 172:239-53.

Wolf Bryant, P., Ceman, S., Sant, A. J., and H. L. Ploegh. (1999). Deviant trafficking of I-Ad mutant molecules is reflected in their peptide binding properties. Eur. J. Immunol. 9: 2729-39.

Driessen, C., Bryant, R. A. R., Lennon-Dumenil, A -M., Villadangos, J. A., Bryant, P. W., Shi, G. -P., Chapman, H. A., and H. L. Ploegh. (1999). Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells. J. Cell Biol. 147:775-90.

Rodgers, J. R., Levitt, J., M., Cresswell, P., Lindahl, K. F., Mathis, D., Monaco, J. T., Singer, D. S., Ploegh, H. L., and P. Wolf Bryant. (1999). A nomenclature solution to mouse MHC confusion. J. Immunol. 162: 6294.

Wolf, P. R., Tourne, S., Miyazaki, T., Benoist, C., Mathis, D., and H. Ploegh. (1998). The phenotype of H-2M deficient mice is dependent on the class II molecules expressed. Eur. J. Immunol. 28: 2605-2618.

Wilson, N. A., Wolf, P., Ploegh, H., Ignatowicz, L., Kappler, J., and P. Marrack. (1998). Invariant chain can bind MHC class II at a site other than the peptide binding groove. J.Immuol. 161:4777-84.

Tourne, S., Miyazaki, T., Wolf, P., Ploegh, H., Benoist, C., and D. Mathis. (1997). Functionality of major histocompatibility complex class II molecules in mice doubly deficient for invariant chain and H-2M complexes. Proc. Natl. Acad. Sci. USA. 94: 9255-60.

Miyazaki, T., Wolf, P., Tourne, S., Waltzinger, C., Dierich, A., Barois, N., Ploegh, H., Benoist, C., and D. Mathis. (1996). Mice lacking H-2M complexes, enigmatic elements of the MHC class II peptide-loading pathway. Cell. 84: 531-41.

Riese, R. J., Wolf, P. R., Bromme, D., Natkin, L. R., Villadangos, J. A., Ploegh, H. L., and H. A. Chapman. (1996). Essential role for cathepsin S in MHC class II-associated invariant chain processing and peptide loading. Immunity. 4: 357-66.

Wolf, P. R., and H. L. Ploegh. (1995). How MHC class II molecules acquire peptide cargo: Biosynthesis and trafficking through the endocytic pathway. Annu. Rev. Cell Dev. Biol. 11: 267-306.

Wolf, P. R., and H. L. Ploegh. (1995). DM exchange mechanism. Nature. 376: 464-65.

Wolf, P. R., and R. G. Cook. (1995). The class I-b molecule Qa-1 forms heterodimers with H-2Ld and a novel 50-kD glycoprotein encoded centromeric to I-Eb. J. Exp. Med. 181: 657-68.

Wolf, P. R., and R. G. Cook. (1990). The TL region gene 37 encodes a Qa-1 antigen. J. Exp. Med. 172: 1795-1804.

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