The T-cell receptor repertoires expressed by CD4+ and CD4- large granular lymphocytes derived from the same patients suggest the persistent action of an immune-mediated selection process

The lymphoproliferative syndrome with large granular lymphocytes (LGL) is an heterogeneous disorder of unknown etiology. The analysis of T- cell receptor (TCR) genes rearrangements has shown that, in most cases, the disease is associated with clonal proliferation of CD8+CD57+ LGL. However, the putative neoplastic nature of these expansions remains questionable because clonal proliferations of CD8+ cells have recently been found also in physiologic conditions. To obtain more precise information on the mechanisms responsible for LGL expansions, we decided to compare the molecular characteristics of TCRBV chains expressed by LGL with different phenotype and function, but derived from the same patients. To this end, we characterized, at the molecular level, the TCR repertoires of fractionated T-cell populations of two unusual patients with concurrent expansions of CD4+CD57+ and CD4-CD57+ LGL. Our results show that the dominant TCRBV chains expressed by the different CD4+ and CD4- LGL populations were strictly oligoclonal. However, the molecular characteristics of the dominant V-D-J rearrangements also imply that the selection of these clones was not due to a neoplastic event. Rather, our data suggest that these particular LGL proliferations can be ascribed to a chronic T-cell- mediated immune response that involves recognition by the engaged TCR of antigens that are not necessarily presented to immune system in the classical major histocompatibility complex-restricted pathway.

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T cell receptor complexes containing Fc epsilon RI gamma homodimers in lieu of CD3 zeta and CD3 eta components: a novel isoform expressed on large granular lymphocytes.

Journal of Experimental Medicine ◽

10.1084/jem.175.1.203 ◽

1992 ◽

Vol 175 (1) ◽

pp. 203-209 ◽

Cited By ~ 44

Author(s):

S Koyasu ◽

L D'Adamio ◽

A R Arulanandam ◽

S Abraham ◽

L K Clayton ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

T Cell Subsets ◽

Large Granular Lymphocytes ◽

Receptor Complexes ◽

Tcr Signal Transduction ◽

High Affinity Receptor ◽

Alpha Beta ◽

Granular Lymphocytes

CD3 zeta and CD3 eta form disulfide-linked homo- or heterodimers important in targeting partially assembled Ti alpha-beta/CD3 gamma delta epsilon T cell receptor (TCR) complexes to the cell surface and transducing stimulatory signals after antigen recognition. Here we identify a new TCR isoform expressed on splenic CD2+, CD3/Ti alpha-beta+, CD4-, CD8-, CD16+, NK1.1+ mouse large granular lymphocytes (LGL), which are devoid of CD3 zeta and CD3 eta proteins. The TCRs of this subset contain homodimers of the gamma subunit of the high affinity receptor for IgE (Fc epsilon RI gamma) in lieu of CD3 zeta and/or CD3 eta proteins. The LGL display natural killer-like activity and are cytotoxic for B cell hybridomas producing anti-CD3 epsilon and anti-CD16 monoclonal antibodies, demonstrating the signaling capacity of both TCR and CD16 in this cell type. These findings provide evidence for an additional level of complexity of TCR signal transduction isoforms in naturally occurring T cell subsets.

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T-cell receptor gene rearrangements and expression in normal human large granular lymphocytes (LGL) and their pathological expansions

Cytotechnology ◽

10.1007/bf00351128 ◽

1987 ◽

Vol 1 (1) ◽

pp. 79-81

Author(s):

Anna Pirelli ◽

Paola Allavena ◽

Alessandro Rambaldi ◽

Maria Di Bello ◽

Paola Pirovano ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Receptor Gene ◽

Cell Receptor ◽

Gene Rearrangements ◽

Large Granular Lymphocytes ◽

Normal Human ◽

T Cell Receptor Gene ◽

Granular Lymphocytes ◽

Cell Receptor Gene

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Analysis of the methylation state of the T cell receptor β chain gene in T cells and large granular lymphocytes

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)31251-6 ◽

1989 ◽

Vol 264 (1) ◽

pp. 251-258

Author(s):

S Sakamoto ◽

J R Ortaldo ◽

H A Young

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Chain Gene ◽

Large Granular Lymphocytes ◽

Methylation State ◽

Β Chain ◽

Granular Lymphocytes

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Clonally expanded CD3+, CD4−, CD8− cells bearing the or the T-cell receptor in patients with the lymphoproliferative disease of granular lymphocytes

Clinical Immunology and Immunopathology ◽

10.1016/0090-1229(91)90094-q ◽

1991 ◽

Vol 60 (3) ◽

pp. 371-383 ◽

Cited By ~ 7

Author(s):

Franco Pandolfi ◽

Robert Foa ◽

Giulio De Rossi ◽

Renato Zambello ◽

Teodoro Chisesi ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Lymphoproliferative Disease ◽

Cd8 Cells ◽

Granular Lymphocytes

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T-cell receptor gene transfer exclusively to human CD8+ cells enhances tumor cell killing

Blood ◽

10.1182/blood-2012-02-412973 ◽

2012 ◽

Vol 120 (22) ◽

pp. 4334-4342 ◽

Cited By ~ 31

Author(s):

Qi Zhou ◽

Irene C. Schneider ◽

Inan Edes ◽

Annemarie Honegger ◽

Patricia Bach ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Gene Transfer ◽

Tumor Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Cell Killing ◽

Specific Gene ◽

Cd8 Cells ◽

Tumor Cell Killing

AbstractTransfer of tumor-specific T-cell receptor (TCR) genes into patient T cells is a promising strategy in cancer immunotherapy. We describe here a novel vector (CD8-LV) derived from lentivirus, which delivers genes exclusively and specifically to CD8+ cells. CD8-LV mediated stable in vitro and in vivo reporter gene transfer as well as efficient transfer of genes encoding TCRs recognizing the melanoma antigen tyrosinase. Strikingly, T cells genetically modified with CD8-LV killed melanoma cells reproducibly more efficiently than CD8+ cells transduced with a conventional lentiviral vector. Neither TCR expression levels, nor the rate of activation-induced death of transduced cells differed between both vector types. Instead, CD8-LV transduced cells showed increased granzyme B and perforin levels as well as an up-regulation of CD8 surface expression in a small subpopulation of cells. Thus, a possible mechanism for CD8-LV enhanced tumor cell killing may be based on activation of the effector functions of CD8+ T cells by the vector particle displaying OKT8-derived CD8-scFv and an increase of the surface density of CD8, which functions as coreceptor for tumor-cell recognition. CD8-LV represents a powerful novel vector for TCR gene therapy and other applications in immunotherapy and basic research requiring CD8+ cell-specific gene delivery.

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Activation via the CD3 and CD16 pathway mediates interleukin-2- dependent autocrine proliferation of granular lymphocytes in patients with granular lymphocyte proliferative disorders

Blood ◽

10.1182/blood.v78.12.3232.3232 ◽

1991 ◽

Vol 78 (12) ◽

pp. 3232-3240 ◽

Cited By ~ 8

Author(s):

S Hoshino ◽

K Oshimi ◽

M Teramura ◽

H Mizoguchi

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Nk Cell ◽

Interleukin 2 ◽

Cell Lineage ◽

Cell Receptor ◽

Cell Phenotype ◽

Beta Chain ◽

Alpha Beta ◽

Granular Lymphocytes

Abstract Granular lymphocytes (GLs) in patients with GL-proliferative disorders (GLPDs) are known to express the interleukin-2 receptor (IL-2R) beta chain (p70–75) constitutively and to proliferate in response to stimulation with IL-2 via the beta chain. In this report, we found that the anti-CD3 monoclonal antibody (MoAb) OKT3 could induce the proliferation of GLs from patients with T-cell lineage GLPDs (T-cell receptor-alpha beta+/CD3+16+), but not that of natural killer (NK) cell lineage GLs (T-cell receptor-alpha beta-/CD3–16+). In contrast, the anti-CD16 MoAb 3G8 that reacts with NK-lineage GLs could induce the proliferation of these GLs but not that of GLs with a T-cell phenotype. Furthermore, the anti-CD16 MoAbs CLB FcR gran1 (VD2) and OK-NK, which react with both T- and NK-lineage GLs, induced the proliferation of GLs with both T- and and NK-cell phenotypes. The proliferative response induced via the CD3 or IgG Fc receptor III (Fc gamma RIII: CD16) pathway was shown to be associated with the IL-2-dependent autocrine pathway by various findings, including the induction of endogenous IL-2 production, the coexpression of the IL-2R alpha chain (p55) and the IL- 2R beta chain, and the inhibition of GL proliferation by anti-IL-2 or anti-IL-2R MoAb. These results suggest that GL proliferation is mediated at least partly through the IL-2-dependent autocrine pathway, and that the TCR/CD3 complex in T-cell phenotype GLs and the Fc gamma RIII in both T- and NK-cell phenotype GLs play a role in their activation in GLPDs.

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T-cell receptor gene rearrangement in T-cell large granular leukocyte leukemia: preferential V alpha but diverse J alpha usage in one of five patients

Blood ◽

10.1182/blood.v83.3.767.767 ◽

1994 ◽

Vol 83 (3) ◽

pp. 767-775 ◽

Cited By ~ 18

Author(s):

C Kasten-Sportes ◽

S Zaknoen ◽

RG Steis ◽

WC Chan ◽

EF Winton ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Selection Process ◽

Receptor Gene ◽

Cell Receptor ◽

Cytotoxic Activities ◽

Beta Chain ◽

Cell Type ◽

Alpha Chain

Abstract T-gamma lymphoproliferative disease (T-gamma LPD) is a chronic disorder of mature T cells that is associated with neutropenia and autoimmune phenomena. Although the progression of the lymphoproliferation is indolent, it is often associated with a monoclonal proliferation of T-cell-type large granular lymphocytes (LGL) that manifest multiple in vitro suppressor and cytotoxic activities. We considered the possibility that the granulocytopenia or anemia might represent an autoimmune disorder mediated by the monoclonal LGL via T-cell receptor (TCR) recognition of an antigen involved in hematopoiesis. Therefore, in an effort to characterize the usage of the TCR alpha-and beta-chain genes in patients with T-gamma LPD, we cloned and sequenced TCR alpha-and beta-chain mRNAs derived from the T-cell type LGL of five patients. The five patients studied did not use a common V alpha nor a common J alpha segment. However, an unusual finding was observed in one of the patients where the occurrence of a single variable-diversity-junctional (VDJ) rearrangement of the beta chain confirmed the monoclonal origin of the LGL proliferation. In accord with this evidence for monoclonality, many of the cells studied used a common V alpha (V alpha 19.1). In contrast to this common V alpha usage, there was a marked diversity of the J alpha segments and N-region addition that were associated with the V alpha 19.1 segment. This pattern of common V alpha usage associated with different N and J alpha segments suggests an immune-mediated selection process affecting the TCR alpha chain occurring after the transformation event that established the clone. We suggest that the T-cell-type LGL malignant clone might have developed autoreactivity conferred by the selected TCR alpha chain and that this autoreactivity might be implicated in this patient's anemia.

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Evidence for in vivo clonal proliferation of unique population of blood CD4-/CD8- T cells bearing T-cell receptor alpha and beta chains in two normal men

Blood ◽

10.1182/blood.v79.11.2965.2965 ◽

1992 ◽

Vol 79 (11) ◽

pp. 2965-2972 ◽

Cited By ~ 20

Author(s):

Y Kusunoki ◽

Y Hirai ◽

S Kyoizumi ◽

M Akiyama

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Nk Cell ◽

Cell Receptor ◽

Cell Markers ◽

Clonal Proliferation ◽

Alpha Beta

Abstract Rare T lymphocytes bearing CD3 surface antigen and T-cell receptor (TCR) alpha and beta chains, but lacking both CD4 and CD8 antigens, viz, TCR alpha beta+CD4–8- cells, appear at a frequency of 0.1% to 2% in peripheral blood TCR alpha beta+ cells of normal donors. Here we report two unusual cases, found among 100 healthy individuals studied, who showed an abnormally elevated frequency of these T cells, ie, 5% to 10% and 14% to 19%. Southern blot analyses of the TCR alpha beta+CD4–8- clones all showed the identical rearrangement patterns for each individual, demonstrating that these are derivatives of a single T cell. The same rearrangement patterns were also observed for the freshly isolated lymphocytes of TCR alpha beta+CD4-CD8- fraction, which excludes the possible bias in the processes of in vitro cloning. These TCR alpha beta+CD4–8- T cells were found to express other mature T-cell markers such as CD2, CD3, and CD5 antigens, as well as natural killer (NK) cell markers (CD11b, CD16, CD56, and CD57 antigens) for both individuals. Further, although lectin-dependent or redirected antibody- dependent cell-mediated cytotoxicities were observed for both freshly sorted lymphocytes of TCR alpha beta+CD4–8- fraction and in vitro established clones, NK-like activity was not detected.

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