The capacity of the immune system to prevent the expansion of autoreactive B and T cells is a critical step in the prevention of autoimmunity, and T cell anergy may play a role in maintenance of peripheral tolerance. Although there exist many molecules that provide costimulatory signals to T cells, only one signal, that mediated by the T cell surface protein CD28, has been shown to prevent the induction of T cell anergy. Manipulation of costimulatory pathways may provide new approaches to treating autoimmune disease and cancer; however, little is known about the costimulatory requirements of CD28"""""""" T cells which account for up to half of human CD8+, CD4""""""""8"""""""" alphabetaTCR+, and gammadeltaTCR+T cells. In order to understand the pathways of activation used by CD28"""""""" T cells, we have examined the costimulatory requirements of antigen specific human CD4""""""""CD8"""""""" alphabetaTCR+ T cell lines that lack the expression of CD28. Although the T cells recognized antigen presented by both CD1+ monocytes and CD1+ B lymphoblastoid cells (B-LCL), proliferation occurred only when antigen was presented by the CD1+ monocytes. Furthermore, when the T cells were cultured with antigen pulsed CD1+ B-LCL, T cell anergy was induced. This suggested that the CD1+ monocytes expressed a costimulatory molecule that the B- LCL transfectants lacked. The required signal occurs via a CD28- independent mechanism and represents a previously unrecognized pathway of costimulation for T cells. This grant proposes to use human T cell lines that require a non-CD28 costimulatory signal to identify the proteins involved in this novel monocyte dependent costimulatory pathway.
In Aim 1, the costimulatory ligand expressed by CD1+ monocytes will be identified and characterized. Known costimulatory molecules will be examined for their ability to prevent anergy in DN1 T cells. If a known molecule is not identified as the relevant costimulatory molecule, antibo will be generated and screened functionally in order to identify the relevant molecule. Alternately, a method to directly clone the gene encoding the costimulatory molecule will be developed. Finally, the cDNA encoding the costimulatory molecule will be transfected into the nonstimulatory CD1+ B-LCL to determine if it confers the ability to stimulate the proliferation of DN1 T cells.
In Aim II, antigen specific MHC restricted T cell clones that are CD28- will be derived and used to further study this novel costimulatory pathway and ascertain the relevance of this pathway to MHC restricted T cells.

Project Start
1999-04-01
Project End
2000-03-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
15
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Koch-Weser, Susan; Rudd, Rima E; Dejong, William (2010) Quantifying word use to study health literacy in doctor-patient communication. J Health Commun 15:590-602
Simard, Julia F; Karlson, Elizabeth W; Costenbader, Karen H et al. (2008) Perinatal factors and adult-onset lupus. Arthritis Rheum 59:1155-61
Costenbader, Karen H; Feskanich, Diane; Mandl, Lisa A et al. (2006) Smoking intensity, duration, and cessation, and the risk of rheumatoid arthritis in women. Am J Med 119:503.e1-9
Karlson, E W; Costenbader, K H; McAlindon, T E et al. (2005) High sensitivity, specificity and predictive value of the Connective Tissue Disease Screening Questionnaire among urban African-American women. Lupus 14:832-6
Katz, Jeffrey N; Amick 3rd, Benjamin C; Keller, Robert et al. (2005) Determinants of work absence following surgery for carpal tunnel syndrome. Am J Ind Med 47:120-30
Costenbader, Karen H; Kim, Daniel J; Peerzada, Jehanna et al. (2004) Cigarette smoking and the risk of systemic lupus erythematosus: a meta-analysis. Arthritis Rheum 50:849-57
Karlson, Elizabeth W; Liang, Matthew H; Eaton, Holley et al. (2004) A randomized clinical trial of a psychoeducational intervention to improve outcomes in systemic lupus erythematosus. Arthritis Rheum 50:1832-41
Bischoff-Ferrari, H A; Lingard, E A; Losina, E et al. (2004) Psychosocial and geriatric correlates of functional status after total hip replacement. Arthritis Rheum 51:829-35
Iversen, Maura D; Fossel, Anne H; Ayers, Kelly et al. (2004) Predictors of exercise behavior in patients with rheumatoid arthritis 6 months following a visit with their rheumatologist. Phys Ther 84:706-16
Karlson, Elizabeth W; Mandl, Lisa A; Hankinson, Susan E et al. (2004) Do breast-feeding and other reproductive factors influence future risk of rheumatoid arthritis? Results from the Nurses' Health Study. Arthritis Rheum 50:3458-67

Showing the most recent 10 out of 242 publications