Induction of Immunological Tolerance to Islet Allografts

T-cell dependent activation of resting B cells involves the interaction of gp39 on T cells with its receptor, CD40, on B cells. We administered either a combination of T-cell-depleted splenic lymphocytes and anti-gp39 monoclonal antibody or antibody alone to establish islet allografts in mice without continuous immunosuppression. Fully allogeneic H-2q FVB islets were permanently accepted by chemically diabetic H-2b C57BL/6 mice provided that the recipients were pretreated with both T-cell-depleted donor spleen cells and anti-gp39 antibody. Antibody alone was less effective in prolonging allograft survival, but we did observe that anti-gp39 mAb alone can exert an independent, primary effect on islet allograft survival that was dose dependent. Targeting gp39, in combination with lymphocyte transfusion, might prove suitable for tolerance induction and allotransplantation without immunosuppression.

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Induction of immunological tolerance requires that the B cells can respond to the polyclonal B-cell-activating properties of the thymus-independent antigens.

Journal of Experimental Medicine ◽

10.1084/jem.146.1.308 ◽

1977 ◽

Vol 146 (1) ◽

pp. 308-312 ◽

Cited By ~ 17

Author(s):

C Fernandez ◽

G Möller

Keyword(s):

B Cells ◽

B Cell ◽

Tolerance Induction ◽

Immunological Tolerance ◽

Spleen Cells ◽

Normal Cells ◽

Purified Protein Derivative ◽

High Affinity

Mice were rendered specifically tolerant to the fluorescein isothiocyanatedextran (FITC) epitope by injection of FITC-dextran B512. Their spleen cells were removed at various times and cultivated in vitro with different polyclonal B-cell activators, such as lipopolysaccharide (LPS), purified protein derivative of tuberculin, and native dextran. LPS caused the appearance of high affinity anti-FITC plaque-forming cells to an equal extent with cells from untreated and tolerant animals, whereas native dextran failed to activate cells from tolerant mice, although it was a potent activator of normal cells. It was concluded that tolerance induction only affects those B cells that could respond to the polyclonal B-cell-activating properties of the tolerogen, but not other B cells having an identical set of Ig receptors directed against the tolerogen.

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IMMUNOLOGICAL TOLERANCE IN BONE MARROW-DERIVED LYMPHOCYTES

Journal of Experimental Medicine ◽

10.1084/jem.139.6.1464 ◽

1974 ◽

Vol 139 (6) ◽

pp. 1464-1472 ◽

Cited By ~ 26

Author(s):

David H. Katz ◽

Toshiyuki Hamaoka ◽

Baruj Benacerraf

Keyword(s):

T Cell ◽

B Cells ◽

Cell Function ◽

Critical Role ◽

Tolerance Induction ◽

Immunological Tolerance ◽

Antigenic Determinants ◽

Humoral Responses

The present studies were designed to probe the role(s) of T cells in preventing or altering tolerance induction in hapten-specific B cells. This was accomplished by using hapten conjugates of normally immunogenic heterologous carriers to selectively inhibit 2,4-dinitrophenyl (DNP)-primed B cells in adoptive transfer experiments in vivo. The data provide strong indications that one critical role of T-cell participation in humoral responses to antigens is to circumvent the development of a tolerogenic signal that, in the absence of such T-cell function, might otherwise ensue after binding of the antigenic determinants by specific precursor B lymphocytes.

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In vitro tolerance induction of primed, IgD-negative murine spleen cells.

Journal of Experimental Medicine ◽

10.1084/jem.153.3.653 ◽

1981 ◽

Vol 153 (3) ◽

pp. 653-664 ◽

Cited By ~ 6

Author(s):

S M Walker ◽

W O Weigle

Keyword(s):

B Cells ◽

Tolerance Induction ◽

Keyhole Limpet Hemocyanin ◽

Immunological Tolerance ◽

Target Cells ◽

Spleen Cells ◽

Murine Spleen ◽

In Vitro Response

The above observations demonstrated induction of immunological tolerance in vitro in primed IgD-, IgG+ B cells. In these studies, addition of trinitrophenylated (TNP) turkey gammaglobulin (TGG) or TNP ovalbumin conjugates suppressed the secondary in vitro response in mice primed with TNP keyhole limpet hemocyanin (TNP-KLH). Suppression was not a reflection of a shift in kinetics of the antibody response, was not dependent on suppressor T cells, and could only be eliciate when conjugate was added within 4 h of addition of TNP-KLH moreover, preincubation of the primed spleen cells with TNP-TGG for 20 h at 37 degrees C, followed by extensive washing, was as effective in inhibiting the response to TNP-KLH as when TNP-TGG was present throughout the 5 d of culture, reflecting induction of a tolerant state. Amounts of conjugate in the concentration range that have been shown by others to tolerize immature or neonatal B cells or mature B cells that have been stripped of surface IgD were sufficient to induce tolerance. The target cells being tolerized did not bear IgD, as determined by B cell depletion and blocking procedures with anti IgD. Whether the lack of surface IgD on the primed cells contributed to the relative ease of tolerance induction was not established by these studies, but the advantages of using primed B cells to examine further the role of surface IgD in tolerance susceptibility was discussed.

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A MOUSE B-CELL ALLOANTIGEN DETERMINED BY GENE(S) LINKED TO THE MAJOR HISTOCOMPATIBILITY COMPLEX

Journal of Experimental Medicine ◽

10.1084/jem.138.6.1289 ◽

1973 ◽

Vol 138 (6) ◽

pp. 1289-1304 ◽

Cited By ~ 186

Author(s):

David H. Sachs ◽

James L. Cone

Keyword(s):

Major Histocompatibility Complex ◽

Lymph Node ◽

T Cell ◽

B Cells ◽

Cell Surface ◽

B Cell ◽

Surface Antigen ◽

Major Histocompatibility ◽

Spleen Cells ◽

Histocompatibility Complex

Antibodies cytotoxic for only a subpopulation of C57Bl/10 lymph node and spleen cells were detected when rat antiserum against B10.D2 was exhaustively absorbed with B10.A lymphocytes. Antibodies of similar specificity were also detected in B10.A anti-B10.D2 and in B10.A anti-C57Bl/10 alloantisera. Reactions with recombinant strains of mice indicate that the cell-surface antigen(s) responsible for this specificity is determined by gene(s) in or to the left of the Ir-1 region of the major histocompatibility complex. A variety of criteria implicate B cells as the subpopulation of lymphocytes bearing this antigen. In view of these data and the recent report by others of a T-cell alloantigen determined by gene(s) in the major histocompatibility complex, it seems possible that there may be a variety of H-2-linked alloantigens expressed preferentially on subclasses of lymphocytes.

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A novel type of cell death of lymphocytes induced by a monoclonal antibody without participation of complement.

Journal of Experimental Medicine ◽

10.1084/jem.181.6.2007 ◽

1995 ◽

Vol 181 (6) ◽

pp. 2007-2015 ◽

Cited By ~ 27

Author(s):

S Matsuoka ◽

Y Asano ◽

K Sano ◽

H Kishimoto ◽

I Yamashita ◽

...

Keyword(s):

Monoclonal Antibody ◽

Cell Death ◽

T Cell ◽

B Cells ◽

Interleukin 2 ◽

Cytolytic Activity ◽

Target Cells ◽

T And B Cells ◽

Fab Fragments ◽

T Cell Clone

A monoclonal antibody, RE2, raised by immunizing a rat with cell lysate of a mouse T cell clone, was found to directly kill interleukin 2-dependent T cell clones without participation of serum complement. Fab fragments of RE2 had no cytolytic activity, while the cross-linking of Fab fragments with anti-rat immunoglobulin reconstituted the cytotoxicity. The cytotoxicity was temperature dependent: the antibody could kill target cells at 37 degrees C but not at 0 degrees C. Sodium azide, ethylenediaminetetraacetic acid, and forskolin did not affect the cytolytic activity of RE2, while the treatment of target cells with cytochalasin B and D completely blocked the activity. This suggested that the cell death involves a cytoskeleton-dependent active process. Giant holes on the cell membrane were formed within 5 minutes after the treatment with RE2, as observed by scanning electron microscopy. There was no indication of DNA fragmentation nor swelling of mitochondria during the cytolysis, suggesting that the cell death is neither apoptosis nor typical necrosis. The antibody also killed T cell lymphomas and T and B cell hybridomas only when these cells were preactivated with concanavalin A, lipopolysaccharide, or phorbol myristate acetate. Preactivated peripheral T and B cells were sensitive to the cytotoxicity of RE2, while resting T and B cells were insensitive. These results provide evidence for a novel pathway of cell death of activated lymphocytes by membrane excitation.

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The role of H-2-linked genes in helper T cell function. VII. Expression of I region and immune response genes by B cells in bystander help assays.

Journal of Experimental Medicine ◽

10.1084/jem.152.5.1274 ◽

1980 ◽

Vol 152 (5) ◽

pp. 1274-1288 ◽

Cited By ~ 31

Author(s):

P Marrack ◽

J W Kappler

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cell Function ◽

High Responder ◽

Helper T Cells ◽

Spleen Cells ◽

Region Gene ◽

Immunoglobulin Receptor

The mode of action by bystander helper T cells was investigated by priming (responder X nonresponder) (B6A)F1 T cells with poly-L-(Tyr, Glu)-poly-D,L-Ala--poly-L-Lys [(TG)-A--L] and titrating the ability of these cells to stimulate an anti-sheep red blood cell (SRBC) response of parental B cells and macrophages in the presence of (TG)-A--L. Under limiting T cell conditions, and in the presence of (TG)-A--L, (TG)-A--L-responsive T cells were able to drive anti-SRBC responses of high-responder C57BL/10.SgSn (B10) B cells and macrophages (M0), but not of low-responder (B10.A) B cells and M0. Surprisingly, the (TG)-A--L-driven anti-SRBC response of B10.A B cells was not restored by addition of high-responder acessory cells, in the form of (B6A)F1 peritoneal or irradiated T cell-depleted spleen cells, or in the form of B10 nonirradiated T cell-depleted spleen cells. These results suggested that (TG)-A--L-specific Ir genes expressed by B cells controlled the ability of these cells to be induced to respond to SRBC by (TG)-A--L-responding T cells, implying that direct contact between the SRBC-binding B cell precursor and the (TG)-A--L-responsive helper T cells was required. Analogous results were obtained for keyhold limpet hemocyanin (KLH)-driven bystander help using KLH-primed F1 T cells restricted to interact with cells on only one of the parental haplotypes by maturing them in parental bone marrow chimeras. It was hypothesized that bystander help was mediated by nonspecific uptake of antigen [(TG)-A--L or KLH] by SRBC-specific b cells and subsequent display of the antigen on the B cell surface in association with Ir of I-region gene products, in a fashion similar to the M0, where it was then recognized by helper T cells. Such an explanation was supported by the observation that high concentrations of antigen were required to elicit bystander help. This hypothesis raises the possibility of B cell processing of antigen bound to its immunoglobulin receptor and subsequent presentation of antigen to helper T cells.

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Germinal center B cell development has distinctly regulated stages completed by disengagement from T cell help

eLife ◽

10.7554/elife.19552 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 20

Author(s):

Ting-ting Zhang ◽

David G Gonzalez ◽

Christine M Cote ◽

Steven M Kerfoot ◽

Shaoli Deng ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

B Cell Differentiation ◽

B Cell Maturation ◽

Germinal Center B Cell ◽

T Cell Help ◽

Dose Dependent

To reconcile conflicting reports on the role of CD40 signaling in germinal center (GC) formation, we examined the earliest stages of murine GC B cell differentiation. Peri-follicular GC precursors first expressed intermediate levels of BCL6 while co-expressing the transcription factors RelB and IRF4, the latter known to repress Bcl6 transcription. Transition of GC precursors to the BCL6hi follicular state was associated with cell division, although the number of required cell divisions was immunogen dose dependent. Potentiating T cell help or CD40 signaling in these GC precursors actively repressed GC B cell maturation and diverted their fate towards plasmablast differentiation, whereas depletion of CD4+ T cells promoted this initial transition. Thus while CD40 signaling in B cells is necessary to generate the immediate precursors of GC B cells, transition to the BCL6hi follicular state is promoted by a regional and transient diminution of T cell help.

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Mature B Cells Are Critical to T-cell-mediated Tumor Immunity Induced by an Agonist Anti-GITR Monoclonal Antibody

Journal of Immunotherapy ◽

10.1097/cji.0b013e3181ee6ba9 ◽

2010 ◽

Vol 33 (8) ◽

pp. 789-797 ◽

Cited By ~ 21

Author(s):

Pengfei Zhou ◽

Junzhuan Qiu ◽

Lawrence LʼItalien ◽

Danling Gu ◽

Douglas Hodges ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

B Cells ◽

Tumor Immunity

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MATURATION OF THE HUMORAL IMMUNE RESPONSE IN MICE

Journal of Experimental Medicine ◽

10.1084/jem.139.2.249 ◽

1974 ◽

Vol 139 (2) ◽

pp. 249-263 ◽

Cited By ~ 92

Author(s):

Patricia G. Spear ◽

Gerald M. Edelman

Keyword(s):

T Cell ◽

B Cells ◽

Cell Function ◽

Spleen Cells ◽

Con A ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Humoral Antibodies

In spite of the prenatal appearance of immunoglobulin-bearing lymphocytes and θ-positive lymphocytes in the spleens of Swiss-L mice, these mice are not able to produce detectable levels of humoral antibodies in response to antigen until after 1 wk of age. Adult levels of response are not achieved until 4–8 wk of age. In the presence of bacterial lipopolysaccharides, which can substitute for or enhance T-cell function, the B cells from young Swiss-L mice were found to be indistinguishable in function from adult B cells, both with respect to the numbers of plaque-forming cells (PFC) produced in vitro in response to antigen and with respect to the kinetics of PFC induction. The spleen cells from young Swiss-L mice are significantly less sensitive than adult spleen cells, however, to stimulation by the T cell mitogens, concanavalin A (Con A) and phytohemagglutinin (PHA). Very few Con A-responsive cells could be detected at birth but the numbers increased sharply with age until 3 wk after birth. On the other hand, PHA-responsive cells could not be detected in the spleen until about 3 wk of age. The latter cells were found to respond also to Con A, but at a lower dose (1 µg/ml) than that required for the bulk of the Con A-responsive cells (3 µg/ml). The cells that respond both to PHA and to Con A appear in the spleen at about the time that Swiss-L mice acquire the ability to produce humoral antibodies, and these cells can be depleted from the spleen by the in vivo administration of antithymocyte serum. The development of humoral immune responses in these mice therefore appears to be correlated with the appearance of recirculating T lymphocytes that are responsive both to PHA and to Con A.

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