Generation of IL-2-dependent cytolytic T lymphocytes (CTLs) with altered TCR responses derived from antigen-dependent CTL clones.
Ag-specific CD8+ CTL clones require TCR stimulation to respond to IL-2 for growth. Because IL-2 may be produced in the vicinity of CD8+ CTLs when Ag is limiting at the end of an immune response, we have examined the effect of culturing viral-specific CTL clones in IL-2 in the absence of antigenic stimulation. Limiting dilution analysis revealed a high precursor frequency for CTL clones derived from IL-2 propagation (termed CTL-factor dependent (FD)) that are dependent upon exogenous IL-2 for growth and survival and no longer require TCR stimulation to proliferate. Culturing CTL-FDs with infected splenocytes presenting Ag and IL-2 did not revert the clones but did lead to a TCR-induced inhibition of proliferation. The derived CTL-FDs have lost the ability to kill via the perforin/granule exocytosis mechanism of killing, although they express similar levels of TCR, CD3epsilon, CD8alphabeta, CD45, and LFA-1 compared with the parental clones. The CTL-FDs retain Fas ligand/Fas-mediated cytotoxicity, and IFN-gamma production and regulate the expression of CD69 and IL-2Ralpha when triggered through the TCR. A parental CTL protected BALB/c mice from a lethal challenge of influenza virus, whereas a CTL-FD did not. These findings represent a novel regulatory function of IL-2 in vitro that, if functional in vivo, may serve to down-regulate cellular immune responses.
Gullo
C A
CA
Department of Microbiology, Beirne B. Carter Center for Immunology Research, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Esser
M T
MT
Fuller
C L
CL
Lam Braciale
V
V
D000281:Administration, Intranasal; D000818:Animals; D000956:Antigens, Viral / Q000008:administration & dosage / Q000502:physiology*; D018929:Cell Culture Techniques / Q000379:methods; D002455:Cell Division / Q000276:immunology; D002999:Clone Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000032:analysis; D009980:Influenza A virus / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000502:physiology*; D007928:Lethal Dose 50; D007939:Leukemia L1210; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000401:mortality / Q000517:prevention & control; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis*; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D007371:Interferon-gamma