title: CD11b+CD28-CD4+ human T cells: activation requirements and association with HLA-DR alleles.
abstract: Engagement of CD28 induces a major costimulatory pathway required by many CD4+ T cells in addition to activation via the TCR. In the absence of signals provided by CD28, ligation of the TCR alone can induce anergy or apoptosis in CD28+ cells. However, we report here characterization of a distinct subset of CD4+ T cells that are CD28-. Three autoreactive CD4+ human T cell clones that could be activated to produce IL-2 and proliferate by anti-CD3 alone were found to lack expression of CD28. CD28- clones that were activated with anti-CD3 alone were not anergic to restimulation via CD3. The presence of CD28-CD4+ T cells was verified in peripheral blood, and their frequency ranged from 0% to >22% of CD4+ T cells in different individuals. The percentage of CD28-CD4+ T cells in the peripheral blood of 57 individuals was significantly correlated with specific class II MHC alleles. Persons with HLA-DRB1*0401 and DR1 alleles had significantly higher numbers of CD28- T cells, while individuals with HLA-DR2(15) had significantly fewer CD28-CD4+ T cells than the mean. Like the CD28- clones, CD28-CD4+ T cells isolated from peripheral blood proliferated upon CD3 cross-linking in the absence of costimulation. The finding that CD28-CD4+ T cells resist induction of anergy following engagement of the TCR in the absence of conventional costimulation demonstrates one mechanism by which autoreactive T cells can escape processes that censor self-reactivity. The MHC associations observed suggest a relationship with autoimmunity and loss of self-tolerance.
authors.affiliation: Department of Veterans Affairs Medical Center, Nashville, TN 37212, USA.
authors.forename: A
authors.initials: A
authors.lastname: Chapman
authors.forename: S J
authors.initials: SJ
authors.lastname: Stewart
authors.forename: G T
authors.initials: GT
authors.lastname: Nepom
authors.forename: W F
authors.initials: WF
authors.lastname: Green
authors.forename: D
authors.initials: D
authors.lastname: Crowe
authors.forename: J W
authors.initials: JW
authors.lastname: Thomas
authors.forename: G G
authors.initials: GG
authors.lastname: Miller
mesh_terms: D000483:Alleles; D000906:Antibodies; D018106:CD28 Antigens / Q000378:metabolism*; D017252:CD3 Complex; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000145:classification* / Q000276:immunology*; D002999:Clone Cells; D006684:HLA-DR Antigens / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D016177:Macrophage-1 Antigen / Q000378:metabolism*
chemical_list: D000906:Antibodies; D018106:CD28 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D006684:HLA-DR Antigens; D007376:Interleukin-2; D016177:Macrophage-1 Antigen