Quantitative assays for detection of residual T cells of T-depleted human marrow

Blood ◽  
1985 ◽  
Vol 65 (5) ◽  
pp. 1134-1140 ◽  
Author(s):  
PJ Martin ◽  
JA Hansen
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Indirect Immunofluorescence ◽  
Bone Marrow Cells ◽  
Allogeneic Bone ◽  
Dilution Assay ◽  
Limiting Dilution Assay ◽  
Limiting Dilution ◽  
Marrow Cells

Preliminary studies have suggested that depletion of T lymphocytes from donor marrow might be an effective method for preventing acute graft-v- host disease (GVHD) after allogeneic bone marrow transplantation in humans (Lancet 1:369, 472, 1984). However, the minimum degree of T cell depletion required to assure the prevention of GVHD in a population of marrow graft recipients has not been defined, largely because quantitative assays with sufficient sensitivity for detecting small numbers of residual viable T cells have not been developed. We have investigated three methods for the detection and enumeration of T cells after treatment of bone marrow with murine monoclonal anti-T cell antibodies and complement. Cell populations prepared by adding graded numbers of T cells to treated bone marrow were analyzed by immediate indirect immunofluorescence, by indirect immunofluorescence after culture of cells in medium containing phytohemagglutinin (PHA), or by a limiting-dilution assay. Immediate indirect immunofluorescence could reliably detect 300 T cells per 10(5) treated bone marrow cells. Indirect immunofluorescence after culture in PHA was tenfold more sensitive and could reliably detect 30 T cells per 10(5) treated bone marrow cells. The limiting dilution assay could be 300-fold more sensitive than immediate indirect immunofluorescence and 30-fold more sensitive than indirect immunofluorescence after culture in PHA. Sensitive, quantitative assays will be useful in guiding the development of methods for efficient removal of T cells in donor marrow, and will be essential for monitoring and interpreting the results of clinical trials.

scholarly journals Quantitative assays for detection of residual T cells of T-depleted human marrow

Blood ◽  
1985 ◽  
Vol 65 (5) ◽  
pp. 1134-1140 ◽  
Author(s):  
PJ Martin ◽  
JA Hansen
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Indirect Immunofluorescence ◽  
Bone Marrow Cells ◽  
Allogeneic Bone ◽  
Dilution Assay ◽  
Limiting Dilution Assay ◽  
Limiting Dilution ◽  
Marrow Cells

Abstract Preliminary studies have suggested that depletion of T lymphocytes from donor marrow might be an effective method for preventing acute graft-v- host disease (GVHD) after allogeneic bone marrow transplantation in humans (Lancet 1:369, 472, 1984). However, the minimum degree of T cell depletion required to assure the prevention of GVHD in a population of marrow graft recipients has not been defined, largely because quantitative assays with sufficient sensitivity for detecting small numbers of residual viable T cells have not been developed. We have investigated three methods for the detection and enumeration of T cells after treatment of bone marrow with murine monoclonal anti-T cell antibodies and complement. Cell populations prepared by adding graded numbers of T cells to treated bone marrow were analyzed by immediate indirect immunofluorescence, by indirect immunofluorescence after culture of cells in medium containing phytohemagglutinin (PHA), or by a limiting-dilution assay. Immediate indirect immunofluorescence could reliably detect 300 T cells per 10(5) treated bone marrow cells. Indirect immunofluorescence after culture in PHA was tenfold more sensitive and could reliably detect 30 T cells per 10(5) treated bone marrow cells. The limiting dilution assay could be 300-fold more sensitive than immediate indirect immunofluorescence and 30-fold more sensitive than indirect immunofluorescence after culture in PHA. Sensitive, quantitative assays will be useful in guiding the development of methods for efficient removal of T cells in donor marrow, and will be essential for monitoring and interpreting the results of clinical trials.

The Orphan Nuclear Receptor NR2F6 Is a Novel Negative Regulator of T-Cell Development.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 915-915
Author(s):  
Christine V. Ichim ◽  
Dzana Dervovic ◽  
Juan Carlo Zuniga-Pflucker ◽  
Richard A. Wells
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Progenitor Cells ◽  
Nuclear Receptor ◽  
Bone Marrow Cells ◽  
Orphan Nuclear Receptor ◽  
Over Expression ◽  
Competitive Disadvantage ◽  
Marrow Cells

Abstract Abstract 915 The orphan nuclear receptor NR2F6 is a mammalian homologue of the Drosophila seven-up gene that plays key roles in decisions of cell fate in neuroblast and retinal cells. We have previously described a novel role for NR2F6 in decisions of cell fate of mammalian haematopoietic cells of the myeloid cell lineage. We have shown that over-expression of NR2F6 in bone marrow cells impairs differentiation and extends the proliferative capacity of myeloid and early progenitor cells eventually leading to acute myeloid leukaemia (AML), while silencing of NR2F6 expression in AML cell lines causes terminal differentiation and apoptosis. A role of NR2F6 in lymphopoiesis has yet to be identified. Here we describe for the first time a role for NR2F6 in the specification of lymphoid cells. NR2F6 expression is heterogeneous throughout the haematopoietic hierarchy, with expression being highest in long-term repopulating HSCs and generally declining with the differentiation of progenitor cells. We report that over-expression of NR2F6 abrogates the developmental program necessary for T-cell lymphopoiesis. We assessed the effects of NR2F6 on lymphopoiesis in vivo by competitive bone marrow transplantation of NR2F6-IRES-GFP or GFP retrovirally transduced grafts (n=43). Competitive repopulation of lethally irradiated murine hosts with GFP transduced bone marrow cells resulted in successful engraftment and T-cell development, with GFP+ T-cells present in the thymus, and periphery at rates comparable to the percent marked cells in the original graft. However over-expression of NR2F6 placed developing T-cells at a dramatic competitive disadvantage. Six weeks post transplant the proportion of CD3+ cells derived from NR2F6 transduced bone marrow cells was greatly diminished relative to control (more than 10 fold), while at 12 weeks post-transplant we observed an abrogation of CD3+ cells derived from NR2F6 transduced T-cells (with the percentage of NR2F6 transduced CD3+ cells being comparable to staining with IgG control) in both the thymus and periphery. This stark competitive disadvantage was observed in all recipients of NR2F6 transduced grafts. We confirmed that this is not a phenomenon specific to the marker CD3 by analysing a portion of the animals for expression of CD4 and CD8, which again showed a lack of mature t-cells. In a second series of bone marrow transplants, cells transduced with NR2F6 or GFP were purified by fluorescence-activated cell sorting and grafts of 100% transduced cells were transferred by tail vein injection into lethally irradiated recipients. Animals transplanted with NR2F6 transduced bone marrow demonstrated a gross decrease in their thymic size and cellularity (∼10 fold decrease, n=17). Furthermore, the thymus of NR2F6 transduced animals contained a larger proportion of non-transduced, GFP negative residual haematopoietic cells than the vector control animals, corroborating the competitive disadvantage that NR2F6 transduced bone marrow cells face in the thymus. As observed in our previous experiments these animals demonstrated a gross reduction in the proportion of CD3+ cells in the thymus, spleen, lymph nodes and peripheral blood. To rule out the possibility that over-expression of NR2F6 is preventing the trafficking of progenitor cells to the thymus we differentiated NR2F6 or GFP transduced haematopoietic stem cells (lin-,c-kit+,sca-1+) into T-cells in vitro on OP9-DL1 cells. We observed a drastic reduction in the number of cells generated from NR2F6 transduced stem/progenitor cells (>50 fold at day 23), suggesting that expression of NR2F6 greatly impairs T-cell development. Mechanistically, others have shown that NR2F6 functions as a transcriptional repressor inhibiting the transactivating ability of genes such as Runx1. We conjecture that in lymphoid progenitors as well NR2F6 functions as a transcriptional repressor preventing the activation of pathways necessary for T-cell survival, proliferation and lymphopoiesis. Taken together, these data establish that the orphan nuclear receptor NR2F6 is a novel negative regulator of T-cell lymphopoiesis, and demonstrate that down-regulation of NR2F6 is important for the survival and proliferation of T-cell progenitors. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Long-lasting skin allograft tolerance in adult mice induced across fully allogeneic (multimajor H-2 plus multiminor histocompatibility) antigen barriers by a tolerance-inducing method using cyclophosphamide.

1989 ◽  
Vol 169 (1) ◽  
pp. 213-238 ◽  
Author(s):  
H Mayumi ◽  
R A Good
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Cells ◽  
Effector T Cells ◽  
Mixed Chimerism ◽  
Allogeneic Bone ◽  
Spleen Cells ◽  
Skin Allograft ◽  
Cell Injection ◽  
Marrow Cells

A new method of cyclophosphamide (CP)-induced skin allograft tolerance in mice that can regularly overcome fully allogeneic (major H-2 plus non-H-2) antigen barriers in mice has been established. The components of the method are intravenous or intraperitoneal administration of 50-100 micrograms of anti-Thy-1.2 mAb on day -1, intravenous injection of 90 x 10(6) allogeneic spleen cells mixed with 30 x 10(6) allogeneic bone marrow cells from the same donor on day 0, and intraperitoneal injection of 200 mg/kg CP on day 2. In each of four fully allogeneic donor----recipient combinations, including C3H/HeJ (C3H; H-2k)----C57BL/6J(B6; H-2b), B6----C3H, BALB/cByJ (BALB; H-2d)----B6, and BALB----C3H, long-lasting survival of skin allografts was induced in most of the recipient mice. The specific tolerant state induced was dependent on the doses of the antibody and bone marrow cells used. The optimal timing of CP treatment to induce tolerance was found to be 1-3 d after the stimulating cell injection. Treatment with the anti-Thy-1.2 antibody together with CP on day 2 after the cell injection on day 0 also induced profound tolerance. In the B6 mice made tolerant of C3H with antibody, C3H spleen cells plus C3H bone marrow cells, and then CP, a minimal degree of stable mixed chimerism was established and the antitolerogen (C3H) immune responses examined here, including delayed footpad reaction (DFR), CTL activity, and capacity for antibody production against donor-strain antigens were abrogated in a tolerogen-specific manner. From cell transfer experiments, the mechanism of tolerance could be largely attributed to reduction of effector T cells reactive against the tolerogen, and strong suppressive influences that might prolong skin allograft survival directly were not detected in the tolerant mice. Moreover, pretreatment with anti-Thy-1.2 antibody or anti-L3T4 (CD4) antibody was more effective than pretreatment with anti-Lyt-1 (CD5) antibody or anti-Lyt-2 (CD8) antibody as an initial step in tolerance induction. These results suggest that permanent tolerance to fully allogeneic skin grafts may be induced because antibody given before the stimulating cell injection reduces the number of reactive T cells in the recipient mice. This antibody treatment may facilitate an antigen-stimulated destruction of responding and thus proliferating cells with CP by preventing a possibly less proliferative, more rapid maturation of reactive T cells or by destroying residual effector T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Production of auto-antiidiotypic antibody during the normal immune response. VII. Analysis of the cellular basis for the increased auto-antiidiotype antibody production by aged mice.

1983 ◽  
Vol 157 (5) ◽  
pp. 1635-1645 ◽  
Author(s):  
E A Goidl ◽  
J W Choy ◽  
J J Gibbons ◽  
M E Weksler ◽  
G J Thorbecke ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Bone Marrow Cells ◽  
Aged Mice ◽  
Old Mice ◽  
Marrow Cells ◽  
Young Mice

We have previously shown that old mice produce more hapten-augmentable plaque-forming cells (PFC) than do young animals, suggesting a greater auto-antiidiotype antibody (auto anti-Id) component in their immune response. In the present studies this is confirmed serologically. The marked auto-anti-Id response of aged mice can be transferred to lethally irradiated young recipients with spleen but not bone marrow cells from old donors, suggesting that it is an intrinsic property of their peripheral B cell population and that the distribution of Id arising from the bone marrow of old and young mice is similar. In contrast with young mice the auto-anti-Id response of old animals is relatively T cell-independent and old donors do not show an increase in their ability to transfer an auto-anti-Id response after priming with TNP-F. These observations suggest that old mice behave as if already primed for auto-anti-Id production. Irradiated mice reconstituted with bone marrow cells from either young or old donors together with splenic T cells from old donors generate a relatively large auto-anti-Id response, whereas mice reconstituted with bone marrow from either young or old donors together with splenic T cells from young donors produce few hapten-augmentable PFC. It is suggested that differences in Id expression and auto-anti-Id production are the consequences of the interaction of Id (and anti-Id) arising from the marrow with anti-Id (and Id) present in the peripheral T cell population which serves as a repository of information about shifts in Id distribution, resulting from lifelong interactions with environmental and self-antigens.

scholarly journals Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 841-851 ◽  
Author(s):  
Elaine M. Sloand ◽  
Lori Mainwaring ◽  
Monika Fuhrer ◽  
Shakti Ramkissoon ◽  
Antonio M. Risitano ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Growth ◽  
Myelodysplastic Syndrome ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Cell Contact ◽  
Trisomy 8 ◽  
Marrow Cells

AbstractClinical observations and experimental evidence link bone marrow failure in myelodysplastic syndrome (MDS) with a T cell–dominated autoimmune process. Immunosuppressive therapy is effective in improving cytopenias in selected patients. Trisomy 8 is a frequent cytogenetic abnormality in bone marrow cells in patients with MDS, and its presence has been associated anecdotally with good response to immunotherapy. We studied 34 patients with trisomy 8 in bone marrow cells, some of whom were undergoing treatment with antithymocyte globulin (ATG). All had significant CD8+ T-cell expansions of one or more T-cell receptor (TCR) Vβ subfamilies, as measured by flow cytometry; expanded subfamilies showed CDR3 skewing by spectratyping. Sorted T cells of the expanded Vβ subfamilies, but not of the remaining subfamilies, inhibited trisomy 8 cell growth in short-term hematopoietic culture. The negative effects of Vβ-expanded T cells were inhibited by major histocompatibility complex (MHC) class 1 monoclonal antibody (mAb) and Fas antagonist and required direct cell-to-cell contact. Sixty-seven percent of patients who had de novo MDS with trisomy 8 as the sole karyotypic abnormality responded to ATG with durable reversal of cytopenias and restoration of transfusion independence, with stable increase in the proportion of trisomy 8 bone marrow cells and normalization of the T-cell repertoire. An increased number of T cells with apparent specificity for trisomy 8 cells is consistent with an autoimmune pathophysiology in trisomy 8 MDS.

scholarly journals Thymopoietic and Bone Marrow Response to Murine Pneumocystis Pneumonia

2011 ◽  
Vol 79 (5) ◽  
pp. 2031-2042 ◽  
Author(s):  
Xin Shi ◽  
Ping Zhang ◽  
Gregory D. Sempowski ◽  
Judd E. Shellito
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Host Defense ◽  
Bone Marrow Cells ◽  
Central Memory ◽  
Jnk Pathway ◽  
Content Type ◽  
Enhanced Production ◽  
Marrow Cells

ABSTRACTCD4+T cells play a key role in host defense againstPneumocystisinfection. To define the role of naïve CD4+T cell production through the thymopoietic response in host defense againstPneumocystisinfection,Pneumocystis murinainfection in the lung was induced in adult male C57BL/6 mice with and without prior thymectomy.Pneumocystisinfection caused a significant increase in the number of CCR9+multipotent progenitor (MPP) cells in the bone marrow and peripheral circulation, an increase in populations of earliest thymic progenitors (ETPs) and double negative (DN) thymocytes in the thymus, and recruitment of naïve and total CD4+T cells into the alveolar space. The level of murine signal joint T cell receptor excision circles (msjTRECs) in spleen CD4+cells was increased at 5 weeks post-Pneumocystisinfection. In thymectomized mice, the numbers of naïve, central memory, and total CD4+T cells in all tissues examined were markedly reduced followingPneumocystisinfection. This deficiency of naïve and central memory CD4+T cells was associated with delayed pulmonary clearance ofPneumocystis. Extracts ofPneumocystisresulted in an increase in the number of CCR9+MPPs in the cultured bone marrow cells. Stimulation of cultured bone marrow cells with ligands to Toll-like receptor 2 ([TLR-2] zymosan) and TLR-9 (ODN M362) each caused a similar increase in CCR9+MPP cells via activation of the Jun N-terminal protein kinase (JNK) pathway. These results demonstrate that enhanced production of naïve CD4+T lymphocytes through the thymopoietic response and enhanced delivery of lymphopoietic precursors from the bone marrow play an important role in host defense againstPneumocystisinfection.

Defects in T-cell–mediated immunity to influenza virus in murine Wiskott-Aldrich syndrome are corrected by oncoretroviral vector–mediated gene transfer into repopulating hematopoietic cells

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3108-3116 ◽  
Author(s):  
Ted S. Strom ◽  
Stephen J. Turner ◽  
Samita Andreansky ◽  
Haiyan Liu ◽  
Peter C. Doherty ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Response ◽  
Bone Marrow Cells ◽  
T Cell Response ◽  
Lymphoid Cells ◽  
Wiskott Aldrich Syndrome ◽  
Marrow Cells

AbstractThe Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by immune dysfunction, thrombocytopenia, and eczema. We used a murine model created by knockout of the WAS protein gene (WASP) to evaluate the potential of gene therapy for WAS. Lethally irradiated, male WASP— animals that received transplants of mixtures of wild type (WT) and WASP— bone marrow cells demonstrated enrichment of WT cells in the lymphoid and myeloid lineages with a progressive increase in the proportion of WT T-lymphoid and B-lymphoid cells. WASP— mice had a defective secondary T-cell response to influenza virus which was normalized in animals that received transplants of 35% or more WT cells. The WASP gene was inserted into WASP— bone marrow cells with a bicistronic oncoretroviral vector also encoding green fluorescent protein (GFP), followed by transplantation into irradiated male WASP— recipients. There was a selective advantage for gene-corrected cells in multiple lineages. Animals with higher proportions of GFP+ T cells showed normalization of their lymphocyte counts. Gene-corrected, blood T cells exhibited full and partial correction, respectively, of their defective proliferative and cytokine secretory responses to in vitro T-cell–receptor stimulation. The defective secondary T-cell response to influenza virus was also improved in gene-corrected animals.

scholarly journals CTLA-4 on alloreactive CD4 T cells interacts with recipient CD80/86 to promote tolerance

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3475-3484 ◽  
Author(s):  
Josef Kurtz ◽  
Forum Raval ◽  
Casey Vallot ◽  
Jayden Der ◽  
Megan Sykes
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Bone Marrow Cells ◽  
Antigen Presenting Cells ◽  
Cd4 T Cell ◽  
Cell Tolerance ◽  
Antigen Presenting ◽  
Marrow Cells

Abstract Although the inhibitory receptor CTLA-4 (CD152) has been implicated in peripheral CD4 T-cell tolerance, its mechanism of action remains poorly defined. We analyzed mechanisms of CD4 cell tolerance in a model of tolerance induction involving establishment of mixed hematopoietic chimerism in recipients of fully MHC-mismatched allogeneic bone marrow cells with anti-CD154 mAb. Animals lacking CD80 and CD86 failed to achieve chimerism. We detected no T cell–intrinsic requirement for CD28 for chimerism induction. However, a CD4 T cell–intrinsic signal through CTLA-4 was shown to be essential within the first 48 hours of exposure to alloantigen for the establishment of tolerance and mixed chimerism. This signal must be provided by a recipient CD80/86+ non–T-cell population. Donor CD80/86 expression was insufficient to achieve tolerance. Together, our findings demonstrate a surprising role for interactions of CTLA-4 expressed by alloreactive peripheral CD4 T cells with CD80/86 on recipient antigen-presenting cells (APCs) in the induction of early tolerance, suggesting a 3-cell tolerance model involving directly alloreactive CD4 cells, donor antigen-expressing bone marrow cells, and recipient antigen-presenting cells. This tolerance is independent of regulatory T cells and culminates in the deletion of directly alloreactive CD4 T cells.

scholarly journals Humoral immunity is the dominant barrier for allogeneic bone marrow engraftment in sensitized recipients

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3611-3619 ◽  
Author(s):  
Hong Xu ◽  
Paula M. Chilton ◽  
Michael K. Tanner ◽  
Yiming Huang ◽  
Carrie L. Schanie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Humoral Immunity ◽  
Bone Marrow Cells ◽  
Critical Role ◽  
Cell Mediated Immunity ◽  
Allogeneic Bone ◽  
Donor Skin

Abstract We evaluated the relative contribution of the humoral and cellular arms of the immune response to bone marrow cells transplanted into sensitized recipients. We report here for the first time that humoral immunity contributes predominantly to allosensitization. Although the major role for nonmyeloablative conditioning is to control alloreactive host T cells in nonsensitized recipients, strikingly, none of the strategies directed primarily at T-cell alloreactivity enhanced engraftment in sensitized mice. In evaluating the mechanism behind this barrier, we found that humoral immunity plays a critical role in the rejection of allogeneic marrow in sensitized recipients. Adoptive transfer of as little as 25 μL serum from sensitized mice abrogated engraftment in secondary naive recipients. With the use of μMT mice as recipients, we found that T-cell-mediated immunity plays a secondary but still significant role in allorejection. Targeting of T cells in sensitized B-cell-deficient μMT mice enhanced alloengraftment. Moreover, both T- and B-cell tolerance were achieved in sensitized recipients when allochimerism was established, as evidenced by the acceptance of second donor skin grafts and loss of circulating donor-specific Abs. These findings have important implications for the management of sensitized transplant recipients and for xenotransplantation in which B-cell reactivity is a predominant barrier.

scholarly journals Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: a role for the gut epithelium in T cell differentiation.

1991 ◽  
Vol 173 (2) ◽  
pp. 471-481 ◽  
Author(s):  
D Guy-Grand ◽  
N Cerf-Bensussan ◽  
B Malissen ◽  
M Malassis-Seris ◽  
C Briottet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Antigenic Stimulation ◽  
Gamma Delta ◽  
Gut Epithelium ◽  
Alpha Beta ◽  
Thymectomized Mice ◽  
Marrow Cells

Mouse gut intraepithelial lymphocytes (IEL) consist mainly (90%) of two populations of CD8+ T cells. One bears heterodimeric alpha/beta CD8 chains (Lyt-2+, Lyt-3+), a T cell receptor (TCR) made of alpha/beta chains, and is Thy-1+; it represents the progeny of T blasts elicited in Peyer's patches by antigenic stimulation. The other bears homodimeric alpha/alpha CD8+ chains, contains no beta chain mRNA, and is mostly Thy-1- and TCR-gamma/delta + or -alpha/beta +; it is thymo-independent and does not require antigenic stimulation, as shown by its presence: (a) in nude and scid mice; (b) in irradiated and thymectomized mice repopulated by T-depleted bone marrow cells bearing an identifiable marker; (c) in thymectomized mice treated by injections of monoclonal anti-CD8 antibody, which lead to total depletion of peripheral CD8+ T lymphocytes; and (d) in germ-free mice and in suckling mice. In young nude mice, alpha/alpha CD8 chains, CD3-TCR complexes, and TCR mRNAs (first gamma/delta) are found on IEL, while they are not detectable on or in peripheral or circulating lymphocytes or bone marrow cells. IEL, in contrast to mature T cells, contain mRNA for the RAG protein, which is required for the rearrangement of TCR and Ig genes. We propose that the gut epithelium (an endoderm derivative, as the thymic epithelium) has an inductive property, attracting progenitors of bone marrow origin, and triggering their TCR rearrangement and alpha/alpha CD8 chains expression, thus giving rise to a T cell population that appears to belong to the same lineage as gamma/delta thymocytes and to recognize an antigenic repertoire different from that of alpha/beta CD8+ IEL.

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