scholarly journals Role of Ia antigens in graft vs. host reactions. II. Molecular and functional analysis of T cell alloreactivity by the characterization of host Ia antigens on alloactivated donor T cells.

1982 ◽  
Vol 155 (1) ◽  
pp. 61-82 ◽  
Author(s):  
T L Delovitch ◽  
J F Harris ◽  
R Battistella ◽  
K Kaufman
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Host Cells ◽  
Two Dimensional Gel Electrophoresis ◽  
Ia Antigens ◽  
Donor T Cells ◽  
Helper Activity ◽  
T Cell Subpopulations

Graft vs. host response (GVHR)-activated donor T cells bind to stimulatory host cell-derived Ia antigens. Radioimmune cell-binding assays demonstrate that activated donor T cells acquire both host I-A and I-E alloantigens on their surface. Approximately threefold to fivefold less I-E products than I-A products are transferred. Immunoprecipitation and one-dimensional and two-dimensional gel electrophoresis analyses show that radioiodinated alpha and beta polypeptide chains of both I-A and I-E-encoded host Ia molecules may be transferred in an apparently structurally unaltered form from host cells to donor cells. Biosynthetic studies indicate that [35S]methionine-labeled activated donor T cells do not synthesize Ia antigens of the donor haplotype. Functional analyses with fluorescence-activated cell sorter sorted donor T cell subpopulations show that donor T cells that bind host I-A antigens preferentially cooperate with nonimmune host B cells. Donor T cells that do not bind detectable amounts of host I-A antigens preferentially help nonimmune donor B cells. By contrast, donor T cells that either bind or do not bind host I-A antigens display no H-2-restricted interaction and help both donor and host immune B cells. These data reveal that the Ia antigen-binding specificity of distinct functional subpopulations of alloactivated donor T cells regulates their I-region-restricted (self or allo) helper activity for nonimmune B cells but not immune B cells. Furthermore, they suggest that T cell-macrophage and T cell-B cell collaboration is mediated by a complementary anti-Ia:Ia receptor:ligand type of interaction in which the receptor of a T cell binds to the ligand of an antigen-presenting macrophage and/or B cell.

scholarly journals The histocompatibility restrictions on macrophage T-helper cell interaction determine the histocompatibility restrictions on T-helper cell B-cell interaction.

1978 ◽  
Vol 148 (5) ◽  
pp. 1171-1185 ◽  
Author(s):  
U Yamashita ◽  
E M Shevach
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Interaction ◽  
T Helper Cell ◽  
Helper T Cells ◽  
T Helper ◽  
Ia Antigens ◽  
Nominal Antigen

To study the histocompatibility restriction between macrophages and helper T cells, carrier primed guinea pig T cells were positively selected in vitro with antigenpulsed macrophages for 7 days and the selected T cells were then mixed with hapten-primed B cells and stimulated with antigen in a modified Mishell-Dutton system. Helper T cells could only be selected with syngeneic, but not allogeneic, antigen-pulsed macrophages and would then collaborate only with syngeneic, but not allogeneic, hapten-primed spleen cells. When F1 T cells were selected with antigen-pulsed parental macrophages they would only collaborate with B cells of the same parental strain as the macrophages used in the selection culture. These results are strongly in support of the view that the primed T cell is activated by carrier determinants of the nominal antigen in association with Ia antigens on macrophages and the helper T cell, in turn, activates B cells which bear the same Ia antigens and determinants of the nominal antigen bound to immunoglobulin receptors on their surface. In addition, in experiments with antigens the response to which is controlled by I-linked genes, we demonstrated that primed (responder X nonresponder)F1 T cells would only collaborate with B cells of the responder parent. The defect appeared to be at the level of the B cell in that the addition to the cultures of antigen-presenting cells of the responder type did not restore the ability of F1 T cells to collaborate with non-responder B cells.

scholarly journals Resting and sensitized T lymphocytes exhibit distinct stimulatory (antigen-presenting cell) requirements for growth and lymphokine release.

1984 ◽  
Vol 160 (6) ◽  
pp. 1717-1735 ◽  
Author(s):  
K Inaba ◽  
R M Steinman
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Lymphocytes ◽  
B Cell ◽  
Interleukin 2 ◽  
Specific Antigen ◽  
Histocompatibility Complex ◽  
Ia Antigens ◽  
Antigen Presenting

Previous studies have shown that unprimed or resting T lymphocytes will grow and release lymphokines when stimulated by dendritic cells (DC). We now have examined the stimulatory requirements for antigen-primed or blast-transformed T cells. The latter were derived from dendritic/T cell clusters that developed during the primary mixed leukocyte reaction (MLR). The specificity of the blasts was established by a binding assay in which most T cells aggregated small B lymphocytes of the appropriate haplotype within 2 h at 4 or 37 degrees C. Since unprimed T cells did not aggregate allogeneic B cells, we suggest that DC induce T lymphocytes to express additional functioning receptors for antigen. Lyt-2-T blasts did not grow or release interleukin 2 or B cell helper factors unless rechallenged with specific alloantigen, whereupon growth (generation time of 14-18 h) and lymphokine release rapidly resumed. The blasts could be stimulated by allogeneic macrophages, B cells, and B lymphoblasts, whereas the primary MLR was initiated primarily by DC. responsiveness appeared restricted to the I region of the major histocompatibility complex, and varied directly with the level of Ia antigens on the stimulator cells. The interaction of B cells and T blasts was bidirectional. The T blasts would grow and form B cell helper factors, while the B cells grew and secreted antibody. However, the efficacy of T cell-mediated antibody formation was enhanced some 10-fold by the addition of specific antigen. Therefore, responses of resting helper T cells, then, are initiated by antigen plus DC. Once sensitized, T blasts interact independently with antigen presented by other leukocytes.

scholarly journals Activation and Tolerance in CD4+ T Cells Reactive to an Immunoglobulin Variable Region

2004 ◽  
Vol 200 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Christopher M. Snyder ◽  
Katja Aviszus ◽  
Ryan A. Heiser ◽  
Daniel R. Tonkin ◽  
Amanda M. Guth ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Variable Region ◽  
Cell Receptor ◽  
B Cell Activation ◽  
Antibody Diversity ◽  
Helper Activity

Antibody diversity creates an immunoregulatory challenge for T cells that must cooperate with B cells, yet discriminate between self and nonself. To examine the consequences of T cell reactions to the B cell receptor (BCR), we generated a transgenic (Tg) line of mice expressing a T cell receptor (TCR) specific for a κ variable region peptide in monoclonal antibody (mAb) 36-71. The κ epitope was originally generated by a pair of somatic mutations that arose naturally during an immune response. By crossing this TCR Tg mouse with mice expressing the κ chain of mAb 36-71, we found that κ-specific T cells were centrally deleted in thymi of progeny that inherited the κTg. Maternally derived κTg antibody also induced central deletion. In marked contrast, adoptive transfer of TCR Tg T cells into κTg recipients resulted in T and B cell activation, lymphadenopathy, splenomegaly, and the production of IgG antichromatin antibodies by day 14. In most recipients, autoantibody levels increased with time, Tg T cells persisted for months, and a state of lupus nephritis developed. Despite this, Tg T cells appeared to be tolerant as assessed by severely diminished proliferative responses to the Vκ peptide. These results reveal the importance of attaining central and peripheral T cell tolerance to BCR V regions. They suggest that nondeletional forms of T tolerance in BCR-reactive T cells may be insufficient to preclude helper activity for chromatin-reactive B cells.

Potent B Cell Leukemia-Reactive T Cells Present in Naive Donor T Cell Populations Can Be Isolated under GMP Conditions Using a Universal Stimulation and Isolation Procedure.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3689-3689
Author(s):  
I. Jedema ◽  
J. Olde Wolbers ◽  
E. Steeneveld ◽  
A.-M. Rasmussen ◽  
W.M. Smit ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Isolation Procedure ◽  
Primary Immune Response ◽  
Cell Populations ◽  
Activated T Cells ◽  
Donor T Cells

Abstract Treatment of patients with relapsed or persistent acute lymphoblastic leukemia (ALL) or chronic lymphocytic leukemia (CLL) after allo-SCT with donor lymphocyte infusions (DLI) is frequently unsuccessful, probably due to the limited immunogenicity of these malignant B cells, and the lack of specificity of the T cells. In this study, we generated a broadly applicable stimulation and isolation procedure for the induction of leukemia-reactive T cells under good manufacturing practice (GMP) conditions. First, B-cell leukemias were modified into professional antigen presenting cells (APC). We previously demonstrated that CD40 crosslinking was required for the production of appropriate malignant B cell-APCs. CD40L expressing mouse fibroblasts were potent activators of CD40, but not GMP approved. CD40L trimers and CD40 antibodies crosslinked to plates or beads only minimally triggered CD40 on malignant B cells. As previously demonstrated, activated T cells briefly express CD40L. We first determined the dynamics and kinetics of CD40L expression on peripheral blood (PB) donor T cells after stimulation with CD3/28 Dynal T cell expansion-beads added in a ratio of 1 bead/10 PBMC. The kinetics were highly variable, with the optimal surface expression of CD40L on a median of 20% of the T cells (range 10–35%, n=6) being detectable between day 1 and 5. We next investigated the capacity of these activated T cells to stimulate malignant B cells in PB from patients with ALL or CLL containing 60–95% leukemic cells. We developed a two-step strategy using special CD3/28 Dynal isolation beads applicable not only for T cell activation, but also for T cell isolation. Using these beads, the T cells were depleted from the PB of the patient, directly irradiated and added back to the B cell cultures. After 3–7 days all B cells displayed a good APC phenotype with expression of CD80, CD86, and CD83 in the patient samples containing >5% T cells. If insufficient T cell numbers were present, donor T cells could be used as source of CD40L. Leukemia-reactive T cells could be reproducibly generated after two stimulations of fully HLA matched donor T cells with the leukemic APC under mild stimulatory conditions, followed by isolation of the responding T cells based on their production of interferon gamma (IFNg). Next, we investigated whether the leukemia-reactive T cells were the result of the successful induction of a primary immune response or that recognition of mimicry epitopes by previously activated T cells was underlying the activity. We separated unmodified donor T cells into CD45 RO+ memory cells, CD45RA+/CD27+ naive cells, and CD45RA+/CD27− effector cells by MACS CD45RO depletion, followed by FACS sorting on CD27, and stimulated these fractions with malignant APCs. Whereas high frequencies of IFNg producing T cells (5–15%) with cytotoxic activity against the primary leukemia (20–50% lysis) were induced from the naive T cell population, no leukemia-reactive T cells could be isolated from the memory or effector T cell populations (n=3). In conclusion, T cells stimulated with CD3/28 Dynal beads have a transient expression of CD40L and can be used as an alternative source of CD40L to generate good APC of malignant B cells under GMP conditions. These malignant B cell APCs were capable of inducing efficient priming of primary anti-leukemic immune responses by activating naive donor T cells.

scholarly journals Isolation and characterization of membrane receptors for pokeweed mitogens from mouse lymphocytes

1977 ◽  
Vol 165 (3) ◽  
pp. 431-437 ◽  
Author(s):  
K Yokoyama ◽  
T Terao ◽  
T Osawa
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Membranes ◽  
Membrane Receptors ◽  
Isolation And Characterization ◽  
Ia Antigens ◽  
Affinity Adsorbent ◽  
Cell Mitogen

The major glycoproteins that bind pokeweek B-cell mitogen (Pa-1) and pokeweed T-cell mitogen (Pa-2) were isolated and identified from bone-marrow-derived lymphocytes (B-cells) and thymus-derived lymphocytes (T-cells) of C3H/He mice. The surfaces of the cells were 125I-labelled by using the enzyme lactoperoxidase, and the plasma membranes were isolated from the 125I-labelled cells. These membranes were solubilized with Triton X-100 and subjected to affinity chromatography on the affinity adsorbent prepared by coupling mitogen Pa-1 or Pa-2 to activated Sepharose 4B. The glycoproteins specifically eluted with di-N-acetylchitobiose from the affinity adsorbents were analysed according to their mobility on polyacrylamide-gel electrophoresis in sodium dodecyl sulphate. These glycoproteins were further identified by immunoprecipitation with specific antisera. Immunoglobulins, possibly immunoglobulins M and D, were identified in the eluate from the B-cell membranes, but they were not detected in the eluate from the T-cell membranes. The histocompatibility-2-complex proteins (H-2D, H-2K and Ia antigens) were found to be major receptor sites for the pokeweed mitogens on both B-cells and T-cells. However, mitogen Pa-1 (B-cell) has a stronger affinity to Ia antigens than does mitogen Pa-2 (T-cell).

scholarly journals B Cell Requirement for Robust Regulatory T Cell Responses to Friend Retrovirus Infection

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
Tyler C. Moore ◽  
Lorena M. Gonzaga ◽  
Jennifer M. Mather ◽  
Ronald J. Messer ◽  
Kim J. Hasenkrug
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
T Cell Responses ◽  
Host Cells ◽  
Virus Control ◽  
Cell Responses

ABSTRACTRegulatory T cells (Tregs) are immunosuppressive cells of the immune system that control autoimmune reactivity. Tregs also respond during immune reactions to infectious agents in order to limit immunopathological damage from potent effectors such as CD8+cytolytic T lymphocytes. We have used the Friend virus (FV) model of retroviral infection in mice to investigate how viral infections induce Tregs. During acute FV infection, there is significant activation and expansion of thymus-derived (natural) Tregs that suppress virus-specific CD8+T cell responses. Unlike conventional T cells, the responding Tregs are not virus specific, so the mechanisms that induce their expansion are of great interest. We now show that B cells provide essential signals for Treg expansion during FV infection. Treg responses are greatly diminished in B cell-deficient mice but can be restored by adoptive transfers of B cells at the time of infection. The feeble Treg responses in B cell-deficient mice are associated with enhanced virus-specific CD8+T cell responses and accelerated virus control during the first 2 weeks of infection.In vitroexperiments demonstrated that B cells promote Treg activation and proliferation through a glucocorticoid-induced receptor superfamily member 18 (GITR) ligand-dependent mechanism. Thus, B cells play paradoxically opposing roles during FV infection. They provide proliferative signals to immunsosuppressive Tregs, which slows early virus control, and they also produce virus-specific antibodies, which are essential for long-term virus control.IMPORTANCEWhen infectious agents invade a host, numerous immunological mechanisms are deployed to limit their replication, neutralize their spread, and destroy the host cells harboring the infection. Since immune responses also have a strong capacity to damage host cells and tissues, their magnitude, potency, and duration are under regulatory control. Regulatory T cells are an important component of this control, and the mechanisms that induce them to respond and exert immunosuppressive regulation are of great interest. In the current report, we show that B cells, the cells responsible for making pathogen-specific antibodies, are also involved in promoting the expansion of regulatory T cells during a retroviral infection.In vitrostudies demonstrated that they do so via stimulation of the Tregs through interactions between cell surface molecules: GITR interactions with its ligand (GITRL) on B cells and GITR on regulatory T cells. These findings point the way toward therapeutics to better treat infections and autoimmune diseases.

scholarly journals Analysis of the response of B cells from CBA/N-defective mice to nonspecific T cell help.

1981 ◽  
Vol 154 (5) ◽  
pp. 1608-1617 ◽  
Author(s):  
J L Greenstein ◽  
E Lord ◽  
J W Kappler ◽  
P C Marrack
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Concanavalin A ◽  
Antibody Responses ◽  
Helper Activity ◽  
T Cell Help ◽  
Normal Controls

We have investigated the induction of antibody responses to erythrocyte (RBC)-bound antigens in the (CBA/N x B10)F1 mouse. Male B cells, which express the CBA/N defect, were shown to be unresponsive to RBC antigens when the delivered T cell helper activity was solely nonspecific. Thus we demonstrated that defective B cells did not respond to concanavalin A supernatants or bystander helper activity, in spite of the fact that CBA/N-defective mice could produce these T cell activities. The defective B cell did not respond to RBC-bound antigen in the presence of RBC-primed T cells, although the magnitude of this response was usually twofold less than normal controls. The insensitivity of CBA/N defective B cells to nonspecific T cell helper activities seemed to involve at least the inability of RBC antigens to activate defective B cells in the absence of antigen-specific T cell help.

scholarly journals B cell depletion impairs vaccination-induced CD8+ T cell responses in a type I interferon-dependent manner

2021 ◽  
pp. annrheumdis-2021-220435
Author(s):  
Theresa Graalmann ◽  
Katharina Borst ◽  
Himanshu Manchanda ◽  
Lea Vaas ◽  
Matthias Bruhn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Expansion ◽  
De Novo ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
T Cell Expansion

ObjectivesThe monoclonal anti-CD20 antibody rituximab is frequently applied in the treatment of lymphoma as well as autoimmune diseases and confers efficient depletion of recirculating B cells. Correspondingly, B cell-depleted patients barely mount de novo antibody responses during infections or vaccinations. Therefore, efficient immune responses of B cell-depleted patients largely depend on protective T cell responses.MethodsCD8+ T cell expansion was studied in rituximab-treated rheumatoid arthritis (RA) patients and B cell-deficient mice on vaccination/infection with different vaccines/pathogens.ResultsRituximab-treated RA patients vaccinated with Influvac showed reduced expansion of influenza-specific CD8+ T cells when compared with healthy controls. Moreover, B cell-deficient JHT mice infected with mouse-adapted Influenza or modified vaccinia virus Ankara showed less vigorous expansion of virus-specific CD8+ T cells than wild type mice. Of note, JHT mice do not have an intrinsic impairment of CD8+ T cell expansion, since infection with vaccinia virus induced similar T cell expansion in JHT and wild type mice. Direct type I interferon receptor signalling of B cells was necessary to induce several chemokines in B cells and to support T cell help by enhancing the expression of MHC-I.ConclusionsDepending on the stimulus, B cells can modulate CD8+ T cell responses. Thus, B cell depletion causes a deficiency of de novo antibody responses and affects the efficacy of cellular response including cytotoxic T cells. The choice of the appropriate vaccine to vaccinate B cell-depleted patients has to be re-evaluated in order to efficiently induce protective CD8+ T cell responses.

scholarly journals Disproportion in T-cell subpopulations in immunodeficient mutant hr/hr mice.

1979 ◽  
Vol 149 (1) ◽  
pp. 228-233 ◽  
Author(s):  
A B Reske-Kunz ◽  
M P Scheid ◽  
E A Boyse
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Lymph Nodes ◽  
Salient Feature ◽  
Mutant Gene ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Mice of the HRS strain, which carry the mutant gene hr, were examined for abnormalities in representation of the three T-cell sets Ly1, Ly23, and Ly123 in the spleen. The salient feature of hr/hr mice, which are immunologically deficient, in comparison with +/hr segregants, was a gross disproportion in numbers of cells belonging to the Ly1 and Ly123 sets, at the age of 3--3.5 mo. At this age, Ly123 cells of hr/hr spleen outnumbered Ly1 cells by 2:1, whereas in +/hr spleens Ly123 cells were outnumbered by approximately 1:2. Cells from pooled lymph nodes of hr/hr mice did not show a correspondingly gross disporprotion of Ly1 and Ly123 cells. Total counts of splenic T cells, and of B cells, were not significantly different in hr/hr and +/hr mice.

scholarly journals 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.

1980 ◽  
Vol 152 (5) ◽  
pp. 1274-1288 ◽  
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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