Formation and Function of Human CD28-negative T cells. A central problem in immunology is how Tcell memory is maintained without antigen. CD28-negative """"""""knockout"""""""" mice initiate immune responses but have reduced T cell memory. It is unclear how CD28 is required for initiation and/or maintenance of memory. CD28 co-stimulates T cell responses to antigen, but also stimulates a subset of T cells without antigen (""""""""CD28agonism""""""""). In aging, chronic infection and autoimmunity, up to 75% of human but not mouse CD8+ T cells are CD28-negative. These do not proliferate, associated with immune deficits, including failure to contain HIV. Lack of CD28 may explain proliferative failure of CD28-negative CD8+ T cells, but inhibitory NK receptors onCD28-negative cells might also inhibit proliferation. We hypothesize that CD28 co-stimulates recall responses but also maintains memory T cells without antigen. CD28 agonism is triggered by B7.1 (CDS0) on antigen-presenting cells and by certain monoclonal antibodies. These agonists trigger tyrosine phosphorylation ofCD28, recruit PI3 kinase, sustain expression of CD25 and the NK receptor-family member CD69 and result in T cell proliferation or apoptosis. CD28 agonism also suppresses CD28 transcription. Therefore, CD28agonism might sustain CD28+ memory cells without antigen, but might also drive the formation of CD28-negative T cells. The long-range goal is to understand how expression of and signaling by CD28 contributes toT cell memory.
The Specific Aims are (1) identify genes and T cell subsets responding to CD28 agonism(2) identify the CD28 isoforms and proximal mechanisms for CD28 agonism; (3) construct mice expressingfloxed-huCD28 to permit controlled deletion of CD28 expression in a mouse model. These studies are important for understanding the biology of human memory T cells especially for vaccine design.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI054251-02
Application #
6785382
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Nabavi, Nasrin N
Project Start
2003-08-15
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2006-07-31
Support Year
2
Fiscal Year
2004
Total Cost
$225,750
Indirect Cost
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Medina, Miguel A; Couturier, Jacob; Feske, Marsha L et al. (2012) Granzyme B- and Fas ligand-mediated cytotoxic function induced by mitogenic CD28 stimulation of human memory CD4+ T cells. J Leukoc Biol 91:759-71
Singh, Manisha; Basu, Sreemanti; Camell, Christina et al. (2008) Selective expansion of memory CD4(+) T cells by mitogenic human CD28 generates inflammatory cytokines and regulatory T cells. Eur J Immunol 38:1522-32
Levine, M M; Tacket, C O; Sztein, M B (2001) Host-Salmonella interaction: human trials. Microbes Infect 3:1271-9