Characterization of a novel subset of CD8(+) T cells that expands in patients receiving interleukin-12.
IL-12 has significant antitumor activity in mice that may be mediated by CD8(+) T cells. We show in this report that repeated subcutaneous injections of IL-12 in patients with cancer resulted in the selective expansion of a subset of peripheral blood CD8(+) T cells. This T cell subset expressed high levels of CD18 and upregulated IL-12 receptor expression after IL-12 treatment in vivo. In normal subjects, these CD3(+)CD8(+)CD18(bright) T cells expressed IL-12 and IL-2 receptors and adhesion/costimulatory molecules to a greater degree than other CD8(+) and CD4(+) T cells. They appeared morphologically as large granular lymphocytes, although they did not express NK cell markers such as CD56. In addition, CD8(+)CD18(bright) T cells were almost exclusively T cell receptor (TCR) alphabeta+, and exhibited a TCR Vbeta repertoire that was strikingly oligoclonal, whereas the Vbeta repertoire of CD18(dim) T cells was polyclonal. Although CD8+CD18(bright) T cells demonstrated little functional responsiveness to IL-12 or IL-2 alone in vitro, they responded to the combination of IL-12+IL-2 with strong IFN-gamma production and proliferation and enhanced non-MHC-restricted cytolytic activity. In contrast, CD18(dim) T cells were not activated by IL-12 or IL-2, alone or in combination. These findings demonstrate that CD8+CD18(bright) T cells are a unique population of peripheral blood lymphocytes with features of both memory and effector cells that are capable of TCR-independent activation through combined stimulation with IL-12+IL-2. As this activation results in IFN-gamma production and enhanced cytolytic activity, these T cells may play a role in innate as well as acquired immunity to tumors and infectious pathogens. Additional studies will be necessary to determine whether CD8+CD18(bright) T cells mediate the antitumor effect of IL-12 or IL-2 administered to cancer patients, and if so, whether maximal activation of these T cells with the combination of IL-12+IL-2 in vivo can augment the clinical effectiveness of these cytokines.
Gollob
J A
JA
Department of Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. jgollob@bidmc.harvard.edu
Schnipper
C P
CP
Orsini
E
E
Murphy
E
E
Daley
J F
JF
Lazo
S B
SB
Frank
D A
DA
Neuberg
D
D
Ritz
J
J
D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000648:ultrastructure; D002455:Cell Division / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000494:pharmacology* / Q000627:therapeutic use; D007376:Interleukin-2 / Q000494:pharmacology; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053707:Receptors, Interleukin-12; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000648:ultrastructure; D015854:Up-Regulation / Q000187:drug effects
D007155:Immunologic Factors; D007376:Interleukin-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D015375:Receptors, Interleukin-2; D018664:Interleukin-12; D007371:Interferon-gamma