This proposal examines mechanisms of acquired tolerance to protein antigens with a focus on the antigen presenting cell. The experiments will test the hypothesis that small B cells present antigen to primary helper T cells and turn them off instead of on, because small B cells lack certain accessory signals required by a potentially responsive T cell. This hypothesis offers a satisfactory explanation for the phenomenon of low zone tolerance, in which antigen is introduced in a form which is presented only by antigen-specific small B lymphocytes, bypassing other kinds of APC that are required for a positive response by primary T cells. It may also explain high zone tolerance, since at high antigen concentrations, small B cells can process and present antigens nonspecifically, and they outnumber other class II positive cells. Small B cells may play a role in self tolerance to soluble proteins including immunoglobulins and in transplantation tolerance induced and maintained by allogeneic lymphocytes. Acquired tolerance has obvious potential applications in transplantation, the treatment and prevention of autoimmune disease and chronic infections, and the effective use of the novel therapeutic proteins that can be produced by recombinant DNA techniques. To test the hypothesis: 1. small B cells will be pulsed with antigen in vivo using soluble antigen targeted specifically to membrane IgD, and 2. small B cells from a transgenic mouse expressing a foreign protein antigen will be transfused into syngeneic, non-transgenic mice. In each case, mice will be challenged with antigen in adjuvant and various CD4+ T cell responses will be measured. 3. Class II MHC restriction of helper T cell recognition will be exploited to study the effects of SCID mice (which lack functional B and T lymphocytes) reconstituted with F1 T cells and B cells of a different MHC haplotype from the SCID host. 4. The mechanism of inactivation of CD4+ T cells by B cells actin as APC will be studied in vivo and in vitro using T cells from transgenic mice in which virtually all of the T cells are specific for a particular protein antigen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI029544-03
Application #
3144405
Study Section
Immunobiology Study Section (IMB)
Project Start
1991-01-01
Project End
1993-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Koguchi, Yoshinobu; Thauland, Timothy J; Slifka, Mark K et al. (2007) Preformed CD40 ligand exists in secretory lysosomes in effector and memory CD4+ T cells and is quickly expressed on the cell surface in an antigen-specific manner. Blood 110:2520-7
Wetzel, Scott A; Parker, David C (2006) MHC transfer from APC to T cells following antigen recognition. Crit Rev Immunol 26:1-21
Dullforce, Per A; Seitz, Greg W; Garman, Kiera L et al. (2006) Antigen-specific accumulation of naive, memory and effector CD4 T cells during anterior uveitis monitored by intravital microscopy. Cell Immunol 239:49-60
Wetzel, Scott A; McKeithan, Timothy W; Parker, David C (2005) Peptide-specific intercellular transfer of MHC class II to CD4+ T cells directly from the immunological synapse upon cellular dissociation. J Immunol 174:80-9
Wetzel, Scott A; McKeithan, Timothy W; Parker, David C (2002) Live-cell dynamics and the role of costimulation in immunological synapse formation. J Immunol 169:6092-101
Evans, D E; Munks, M W; Purkerson, J M et al. (2000) Resting B lymphocytes as APC for naive T lymphocytes: dependence on CD40 ligand/CD40. J Immunol 164:688-97
Baird, A M; Parker, D C (1996) Analysis of low zone tolerance induction in normal and B cell-deficient mice. J Immunol 157:1833-9
Yuschenkoff, V N; Sethna, M P; Freeman, G J et al. (1996) Coexpression of B7-1 and antigen blocks tolerance induction to antigen presented by resting B cells. J Immunol 157:1987-95
Lalmanach-Girard, A C; Chiles, T C; Parker, D C et al. (1993) T cell-dependent induction of NF-kappa B in B cells. J Exp Med 177:1215-9
Eynon, E E; Parker, D C (1993) Parameters of tolerance induction by antigen targeted to B lymphocytes. J Immunol 151:2958-64

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