Reversal of hyporesponsiveness in lpr CD4-CD8- T cells is achieved by induction of cell cycling and normalization of CD2 and p59fyn expression.
T cells freshly isolated from the peripheral lymph nodes of autoimmune MRL lpr/lpr (lpr) mice contain a large proportion of functionally non-mature T cell receptor (TcR)-alpha beta+CD3+CD2-CD4-CD8- T cells displaying the B cell isoform of CD45, B220. These cells are hyporesponsive as defined by minimal interleukin-2 (IL-2) production and proliferation in response to stimulation. However, increased levels of inositol phosphates and a rapid mobilization of Ca2+ do occur upon stimulation of the TcR/CD3 complex. Furthermore, lpr CD4-CD8-T cells contain high levels of transcripts for the src-family tyrosine kinase p59fyn, and express a constitutively tyrosine-phosphorylated CD3-zeta chain. These features bear a certain resemblance to anergized T cells. These similarities are extended to show that culturing of lpr CD4-CD8- T cells in the presence of IL-2 in combination with phorbol 12-myristate 13-acetate and ionomycin initiates cell cycling and results in the gain of function; re-stimulation now yields IL-2-dependent proliferation in the absence of exogenous IL-2. In parallel with this gain in function, the population of cells obtained after 1 week in culture retains the TcR-alpha beta + CD4-CD8- phenotype, yet displays increased levels of CD2, decreased surface B220, and normal amounts of p59fyn-specific transcripts. These findings show that cell cycling is associated with the recovery of functional capabilities by lprCD4-CD8-T cells and is closely allied with surface CD2 expression. Thus, the hyporesponsiveness of lpr T cells is not a fixed state.
Clements
J L
JL
Rheumatology and Clinical Immunology Unit, University of Vermont College of Medicine, Burlington 05405.
Wolfe
J
J
Cooper
S M
SM
Budd
R C
RC
D000368:Aged; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D000954:Antigens, Surface / Q000378:metabolism; D018801:CD2 Antigens; D002453:Cell Cycle; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D017493:Leukocyte Common Antigens; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D012333:RNA, Messenger / Q000235:genetics; D011971:Receptors, Immunologic / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D018801:CD2 Antigens; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D015759:Ionomycin; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D017493:Leukocyte Common Antigens; D013755:Tetradecanoylphorbol Acetate