scholarly journals OP0002 IMMTOR NANOPARTICLES ENHANCE THE TOLEROGENIC ENVIRONMENT OF THE LIVER IN MICE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1.1-1
Author(s):  
P. Ilyinskii ◽  
C. Roy ◽  
J. Leprevost ◽  
K. Kishimoto
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Activation ◽  
Large Population ◽  
Tolerance Induction ◽  
Cell Phenotype ◽  
Double Negative ◽  
B Cell Activation ◽  
Liver Sinusoidal Endothelial Cells

Background:Tolerogenic ImmTOR biodegradable nanoparticles encapsulating rapamycin have been shown to mitigate the formation of anti-drug antibodies against pegadricase, a pegylated uricase enzyme, which enabled monthly dosing and sustained reduction of serum uric acid levels in a Phase 2 clinical trial of SEL-212, a combination of pegadricase + ImmTOR, in patients with symptomatic gout with hyperuricemia. Prior mechanism of action studies showed selective biodistribution of ImmTOR to the spleen and liver following intravenous (IV) administration in mice. In the spleen, ImmTOR has been demonstrated to induce tolerogenic dendritic cells and antigen-specific regulatory T cells and inhibit antigen-specific B cell activation. Splenectomized mice showed a partial but incomplete abrogation of the tolerogenic immune response mediated by ImmTOR.Objectives:Here we evaluated the ability of ImmTOR to enhance the tolerogenic environment in the liver.Results:All the major resident populations of liver cells, including liver sinusoidal endothelial cells (LSECs), Kupffer cells (KC), stellate cells (SC), and hepatocytes, actively took up fluorescent-labeled ImmTOR particles, which resulted in downregulation of MHC class II and co-stimulatory molecules and upregulation of the PD-L1 checkpoint molecule. The LSEC, known to play an important role in hepatic tolerance induction, emerged as a key target cell for ImmTOR. The tolerogenic environment led to a multi-pronged modulation of hepatic T cell populations, resulting in an increase in T cells with a regulatory phenotype, upregulation of PD-1 on CD4+ and CD8+ T cells, and the emergence of a large population of CD4–CD8– (double negative) T cell population. Modulation of T cell phenotype was seen to a lesser extent after administration by empty nanoparticles, but not free rapamycin. The upregulation of PD-1, but not the appearance of double negative T cells, was inhibited by antibodies against PD-L1 or CTLA-4.Conclusion:These results suggest that the liver may contribute to the tolerogenic properties of ImmTOR in mitigating anti-drug antibody responses to biologic therapies, such as pegadricase.Disclosure of Interests:Petr Ilyinskii Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Christopher Roy Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Julie LePrevost Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Kei Kishimoto Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences

scholarly journals Enhancement of the Tolerogenic Phenotype in the Liver by ImmTOR Nanoparticles

2021 ◽  
Vol 12 ◽  
Author(s):  
Petr O. Ilyinskii ◽  
Christopher J. Roy ◽  
Julie LePrevost ◽  
Gina L. Rizzo ◽  
Takashi Kei Kishimoto
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Activation ◽  
Large Population ◽  
Cell Phenotype ◽  
Double Negative ◽  
Liver Sinusoidal Endothelial Cells ◽  
Double Negative T Cells

ImmTOR biodegradable nanoparticles encapsulating rapamycin have been shown to induce a durable tolerogenic immune response to co-administered biologics and gene therapy vectors. Prior mechanism of action studies have demonstrated selective biodistribution of ImmTOR to the spleen and liver following intravenous (IV) administration. In the spleen, ImmTOR has been shown to induce tolerogenic dendritic cells and antigen-specific regulatory T cells and inhibit antigen-specific B cell activation. Splenectomy of mice resulted in partial but incomplete abrogation of the tolerogenic immune response induced by ImmTOR. Here we investigated the ability of ImmTOR to enhance the tolerogenic environment in the liver. All the major resident populations of liver cells, including liver sinusoidal endothelial cells (LSECs), Kupffer cells (KC), stellate cells (SC), and hepatocytes, actively took up fluorescent-labeled ImmTOR particles, which resulted in downregulation of MHC class II and co-stimulatory molecules and upregulation of the PD-L1 checkpoint molecule. The LSEC, known to play an important role in hepatic tolerance induction, emerged as a key target cell for ImmTOR. LSEC isolated from ImmTOR treated mice inhibited antigen-specific activation of ovalbumin-specific OT-II T cells. The tolerogenic environment led to a multi-pronged modulation of hepatic T cell populations, resulting in an increase in T cells with a regulatory phenotype, upregulation of PD-1 on CD4+ and CD8+ T cells, and the emergence of a large population of CD4–CD8– (double negative) T cells. ImmTOR treatment protected mice in a concanavalin A-induced model of acute hepatitis, as evidenced by reduced production of inflammatory cytokines, infiltrate of activated leukocytes, and tissue necrosis. Modulation of T cell phenotype was seen to a lesser extent after administration by empty nanoparticles, but not free rapamycin. The upregulation of PD-1, but not the appearance of double negative T cells, was inhibited by antibodies against PD-L1 or CTLA-4. These results suggest that the liver may contribute to the tolerogenic properties of ImmTOR treatment.

Abstract W P87: Characteristics of T-cells Infiltrating Ruptured Intracranial Aneurysm

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Roger M Krzyzewski ◽  
Magdalena K Stachura ◽  
Mariusz Krupa ◽  
Rafal Morga ◽  
Agnieszka Sagan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intracranial Aneurysm ◽  
Peripheral Blood ◽  
Histological Finding ◽  
Cell Phenotype ◽  
Double Negative ◽  
Activation Markers ◽  
Hla Dr ◽  
Ruptured Intracranial Aneurysm

Introduction: Recently the role of adaptive immunity has been implied by microarray studies. But the results are contradictory. T-cell infiltration is a frequent histological finding in ruptured IA, T-cell phenotype, characteristic and true quantitation remains unknown. We preformed a prospective study to determine the subpopulation and expression of activation markers of T-cells infiltrating ruptured IA in relation to peripheral blood. Hypothesis: IA have different subsets and activation levels of T-cells than peripheral blood. Methods: We collected the tissue of ruptured IA of 8 patients operated on within 24 hours after subarachnoid hemorrhage symptoms onset. IA tissue was digested, stained with fluorescently labeled monoclonal antibodies and submitted to flow cytometry. In addition we collected and analyzed venous blood from 6 age, sex and risk factor-matched controls. Results: CD4+ cells are less prevalent in IA tissue than in peripheral blood (42.14±17.28 vs. 65.88±5.32%; p=0.011), while there was no difference in CD8+ T-cells infiltrating IA (30.28±9.07 vs. 27.78±5.45%; p=0.585), and double negative (CD4-CD8-CD3+) T-cells were more prevalent in wall of IA than in circulation, (15.68±11.94 vs. 2.81±1.32%; p=0.026). Importantly, CD4+ infiltrating IA wall showed higher expression of HLA-DR (25.9±6.42 vs. 9.19± 3.58%; p<0.001) higher expression of CD 69 (26.8±19.66 vs. 2.73±0.93%; p=0.014). Similarly, there significantly more CD8+ cells showed HLA-DR+ in the IA than in blood. (45.96±15.57 vs. 22.47±11.46%; p=0.018) and CD69 (30.32±22.73 vs. 5.03±1.55%; p=0.022). Double negative cells in IA also had higher expression of HLA-DR (46.56±21.40 vs. 22.58±5.1%; p=0.025), CD69 (31.05±16.79 vs. 7.83±2.05%; p=0.016). Conclusion: The tissue of ruptured IA is highly infiltrated by T-cells which show high expression of activation markers such as CD69 or HLA-DR. The importance of these cells to immunopathogenesis of intracranial aneurysm rupture should be further characterized.

scholarly journals T Cell Accumulation in B Cell Follicles Is Regulated by Dendritic Cells and Is Independent of B Cell Activation

2003 ◽  
Vol 197 (2) ◽  
pp. 195-206 ◽  
Author(s):  
Simon Fillatreau ◽  
David Gray
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
B Cell Activation ◽  
Cell Accumulation ◽  
Antigen Presenting ◽  
Deficient Mice

We investigated the mechanism of CD4 T cell accumulation in B cell follicles after immunization. Follicular T cell numbers were correlated with the number of B cells, indicating B cell control of the niche that T cells occupy. Despite this, we found no role for B cells in the follicular migration of T cells. Instead, T cells are induced to migrate into B cell follicles entirely as a result of interaction with dendritic cells (DCs). Migration relies on CD40-dependent maturation of DCs, as it did not occur in CD40-deficient mice but was reconstituted with CD40+ DCs. Restoration was not achieved by the activation of DCs with bacterial activators (e.g., lipopolysaccharide, CpG), but was by the injection of OX40L–huIgG1 fusion protein. Crucially, the up-regulation of OX40L (on antigen-presenting cells) and CXCR-5 (on T cells) are CD40-dependent events and we show that T cells do not migrate to follicles in immunized OX40-deficient mice.

scholarly journals T-Cell-Independent Responses to Borrelia burgdorferiAre Critical for Protective Immunity and Resolution of Lyme Disease

2000 ◽  
Vol 68 (9) ◽  
pp. 5190-5197 ◽  
Author(s):  
Maureen D. McKisic ◽  
Stephen W. Barthold
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Activation ◽  
Scid Mice ◽  
Immunoglobulin M ◽  
B Cell Activation ◽  
Challenge Inoculation ◽  
Arthritis Severity ◽  
Immunocompetent Mice ◽  
Deficient Mice

ABSTRACT The humoral immune response to Borrelia burgdorferiduring persistent infection is critical to both protective and disease-resolving immunity. This study examined the role of B cells in the absence of T cells during these events, using mice with selected immune dysfunctions. At 6 weeks postinfection, an interval at which arthritis resolves in immunocompetent mice, arthritis severity was equivalent among immunocompetent mice, αβ+-T-cell-deficient mice, and mice lacking both αβ+ and γδ+ T cells. Arthritis severity was worse in SCID mice, which lack T and B lymphocytes. Carditis regressed in immunocompetent mice and those lacking both αβ+ and γδ+ T cells but remained active in mice lacking only αβ+ T cells and in SCID mice. Mice lacking only αβ+ T cells and those lacking both αβ+ and γδ+ T cells generated immunoglobulin M (IgM) and IgG3 B. burgdorferi-reactive antibodies. Sera from infected immunocompetent mice, mice lacking only αβ+ T cells, and mice lacking both αβ+ and γδ+ T cells passively protected naive mice against challenge inoculation withB. burgdorferi. However, only sera from infected immunocompetent mice, but not sera from infected T-cell-deficient mice, were able to resolve arthritis when passively transferred to actively infected SCID mice. These data demonstrate that B-cell activation during a T-cell-independent response may be critical for resolution of arthritis and carditis and that protective antibodies are generated during this response.

Distinct Patterns of Systemic Immune Dysregulation in Indolent B Cell Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3780-3780
Author(s):  
Petros Christopoulos ◽  
Dietmar Pfeifer ◽  
Kilian Bartholomé ◽  
Marie Follo ◽  
Paul Fisch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Dysregulation ◽  
Cell Phenotype ◽  
Cd4 Cells ◽  
Th Cells

Abstract Mutual interactions of the neoplastic clone with the non-neoplastic immune system may influence immune function and the clinical behaviour of lymphoma. Individuals with immunodeficiency or autoimmune diseases have an increased risk for lymphoma development. The immune microenvironment appears to have a major influence on the prognosis of indolent lymphomas. Conversely, leukemic lymphomas may also cause immunodeficiency: In CLL, direct lymphoma-T cell interactions, which may occur ubiquitously, induce defects in T cell functions (Görgün et al., 2005). We demonstrate here a systemic perturbance of cellular immunity in a prospective study in patients with untreated de novo, limited-stage, non-leukemic indolent B cell lymphomas. Calibrated, quantitative flow cytometry showed a significant reduction of circulating T helper (TH) cells in follicular (FL; n=11; p<0.005) and extranodal marginal zone (eMZL; n=7; p<0.05) lymphomas compared to age-matched healthy persons. Naive TH cells were strongest reduced to 51% (p=0.002) in FL and 24% (p=0.002) in eMZL. Regulatory T cells (CD4loCD25hi; CD4+FoxP3+) were affected less (p=0.04). T cell receptor excision circles within CD4+ cells as assessed by quantitative PCR were not altered in lymphoma patients, indicating neither increased increased thymic output nor homeostatic T cell proliferation to compensate the contracted pool of naive T cells. The TH memory compartments, the global numbers and subsets of CD8+ T (TC) cells, NK, and NKT cells were normal. The peripheral lymphocyte composition was altered differently in early CLL (stage Binet A; leukocyte counts < 28/nl; n=9) with increased TH (p=0.04) and TC (p=0.0002) cells. No significant changes in lymphocyte subsets were noted in monoclonal gammopathy of unknown significance (MGUS; n=6). The functional T cell phenotype in vivo was altered in eMZL as indicated by four- and twofold increased HLA-DR+ TH (p<0.02) and TC (p=0.05) cells. This T cell activation may also explain an increased fraction of terminally differentiated (CD45RA+CD27−) TC cells (p<0.05). Qualitatively similar abnormalities were seen in FL, where activated TH cells were more frequent (p<0.005), and in CLL, where activated TC cells were increased (p=0.04), but not in MGUS. Finally, an increased T cell activation may effect senescence, which was evident by elevated fractions of CD57+ and CD28− cells within the TC compartment of FL/eMZL (p<0.05) and CLL (p<0.005) patients. The activated T cell phenotype was paralleled by increased upregulation of activation markers (CD25, OX40, CD95, p<0.005 for each) and proliferation (p<0.005) by purified CD4 cells from FL/eMZL patients in a standardized anti-CD3/anti-CD28 stimulation culture. None of these parameters was significantly aberrant in CLL. Expression of the activation marker CD69, which is downregulated rapidly after T cell activation, was markedly reduced both in vivo and after in vitro stimulation in FL/eMZL. Collectively, these data demonstrate a global, “preactivated” and presenescent state of peripheral T cells in non-leukemic, indolent T cell lymphomas. Finally, a shift towards TH2 cells was evident in FL/eMZL TH stimulation cultures by increased secretion of IL-4 and IL-5 (p=0.01), but not of IL-2, IFNg, IL-10, and TNFa. This cytokine pattern was absent in CLL and MGUS. The TH2 shift, and the qualitative difference in the immune status in FL/eMZL versus CLL was validated by gene expression profiling of stimulated TH cells with Affymetrix U133 arrays. KEGG annotation revealed decreased expression of proximal TCR signalling molecules and TCR/CD28 transduction pathways with the exception of NFAT in FL/eMZL and CLL. Extensive correlative analyses between gene expression profiles and functional data indicated at least two distinct immune dysregulation patterns: A hyperreactivity/TH2 pattern which is operational even in early disease; and a B cell burden-dependent impairment of TCR signalling. The latter pattern predominates in CLL, which has a comparatively high B cell burden in early disease. These data are clinically relevant since we demonstrate in a prospective trial that untreated FL/eMZL patients fail to respond to protective hepatitis B vaccination (p<0.005). Precise definition of functional T cell defects will permit to study the causes, the prognostic influence, and potential reversibility of immune dysregulation patterns in indolent B cell lymphomas.

scholarly journals Selective immunosuppression by administration of major histocompatibility complex (MHC) class II-binding peptides. I. Evidence for in vivo MHC blockade preventing T cell activation.

1992 ◽  
Vol 175 (5) ◽  
pp. 1345-1352 ◽  
Author(s):  
J C Guéry ◽  
A Sette ◽  
J Leighton ◽  
A Dragomir ◽  
L Adorini
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Specific Class ◽  
Binding Peptide

Draining lymph node cells (LNC) from mice immunized with hen egg white lysozyme (HEL) display at their surface antigen-MHC complexes able to stimulate, in the absence of any further antigen addition, HEL peptide-specific, class II-restricted T cell hybridomas. Chloroquine addition to these LNC cultures fails to inhibit antigen presentation, indicating that antigenic complexes of class II molecules and HEL peptides are formed in vivo. MHC class II restriction of antigen presentation by LNC from HEL-primed mice was verified by the use of anti-class II monoclonal antibodies. Coinjection of HEL and the I-Ak-binding peptide HEL 112-129 in mice of H-2k haplotype inhibits the ability of LNC to stimulate I-Ak-restricted, HEL 46-61-specific T cell hybridomas. Similar results are obtained in mice coinjected with the HEL peptides 46-61 and 112-129. Inhibition of T hybridoma activation can also be observed using as antigen-presenting cells irradiated, T cell-depleted LNC from mice coinjected with HEL 46-61 and HEL 112-129, ruling out the possible role of either specific or nonspecific suppressor T cells. Inhibition of T cell proliferation is associated with MHC-specific inhibition of antigen presentation and with occupancy by the competitor of class II binding sites, as measured by activation of peptide-specific T cell hybridomas. These results demonstrate that administration of MHC class II binding peptide competitors selectively inhibits antigen presentation to class II-restricted T cells, indicating competitive blockade of class II molecules in vivo.

scholarly journals B220+Double-Negative T Cells Suppress Polyclonal T Cell Activation by a Fas-Independent Mechanism That Involves Inhibition of IL-2 Production

2003 ◽  
Vol 171 (5) ◽  
pp. 2421-2426 ◽  
Author(s):  
Abdel Rahim A. Hamad ◽  
Abdiaziz S. Mohamood ◽  
Crystal J. Trujillo ◽  
Ching-Tai Huang ◽  
Emily Yuan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Double Negative ◽  
Independent Mechanism ◽  
Double Negative T Cells

scholarly journals Antigen presentation by resting B cells. Radiosensitivity of the antigen-presentation function and two distinct pathways of T cell activation.

1984 ◽  
Vol 159 (3) ◽  
pp. 881-905 ◽  
Author(s):  
J D Ashwell ◽  
A L DeFranco ◽  
W E Paul ◽  
R H Schwartz
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Antigen Presentation ◽  
Cell Activation ◽  
T Cell Proliferation ◽  
B Cell Activation ◽  
Antigen Presenting

In this report we have examined the ability of small resting B cells to act as antigen-presenting cells (APC) to antigen-specific MHC-restricted T cells as assessed by either T cell proliferation or T cell-dependent B cell stimulation. We found that 10 of 14 in vitro antigen-specific MHC-restricted T cell clones and lines and three of four T cell hybridomas could be induced to either proliferate or secrete IL-2 in the presence of lightly irradiated (1,000 rads) purified B cells and the appropriate foreign antigen. All T cell lines and hybridomas were stimulated to proliferate or make IL-2 by macrophage- and dendritic cell-enriched populations and all T cells tested except one hybridoma caused B cell activation when stimulated with B cells as APC. Furthermore, lightly irradiated, highly purified syngeneic B cells were as potent a source of APC for inducing B cell activation as were low density dendritic and macrophage-enriched cells. Lymph node T cells freshly taken from antigen-primed animals were also found to proliferate when cultured with purified B cells and the appropriate antigen. Thus, small resting B cells can function as APC to a variety of T cells. This APC function was easily measured when the cells were irradiated with 1,000 rads, but was greatly diminished or absent when they were irradiated with 3,300 rads. Thus, the failure of some other laboratories to observe this phenomenon may be the result of the relative radiosensitivity of the antigen-presenting function of the B cells. In addition, this radiosensitivity allowed us to easily distinguish B cell antigen presentation from presentation by the dendritic cell and macrophage, as the latter was resistant to 3,300 rads. Finally, one T cell clone that failed to proliferate when B cells were used as APC was able to recruit allogeneic B cells to proliferate in the presence of syngeneic B cells and the appropriate antigen. This result suggests that there are at least two distinct pathways of activation in T cells, one that leads to T cell proliferation and one that leads to the secretion of B cell recruitment factor(s).

scholarly journals Effects of Friend Virus Infection and Regulatory T Cells on the Antigen Presentation Function of B Cells

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Tyler C. Moore ◽  
Ronald J. Messer ◽  
Lorena M. Gonzaga ◽  
Jennifer M. Mather ◽  
Aaron B. Carmody ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Cell Activation ◽  
T Cell Responses ◽  
B Cell Activation ◽  
Friend Virus ◽  
Cell Responses

ABSTRACTFriend virus (FV) is a naturally occurring mouse retrovirus that infects dividing cells of the hematopoietic lineage, including antigen-presenting cells (APCs). The infection of APCs by viruses often induces their dysfunction, and it has been shown that FV infection reduces the ability of dendritic cells (DCs) to prime critical CD8+T cell responses. Nonetheless, mice mount vigorous CD8+T cell responses, so we investigated whether B cells might serve as alternative APCs during FV infection. Directex vivoanalysis of B cells from FV-infected mice revealed that infected but not uninfected B cells upregulated expression of the costimulatory molecules CD80, CD86, and CD40, as well as major histocompatibility complex class II (MHC-II) molecules. Furthermore,in vitrostudies showed that, compared to uninfected B cells from the same mice, the FV-infected B cells had significantly enhanced APC function, as measured by their capacity to prime CD8+T cell activation and proliferation. Thus, in contrast to DCs, infection of B cells with FV enhanced their APC capacity and ability to stimulate the CD8+T cell responses essential for virus control. FV infections also induce the activation and expansion of regulatory T cells (Tregs), so it was of interest to determine the impact of Tregs on B cell activation. The upregulation of costimulatory molecule expression and APC function of B cells was even more strongly enhanced byin vivodepletion of regulatory T cells than infection. Thus, Tregs exert potent homeostatic suppression of B cell activation that is partially overcome by FV infection.IMPORTANCEThe primary role of B cells in immunity is considered the production of pathogen-specific antibodies, but another, less-well-studied, function of B cells is to present foreign antigens to T cells to stimulate their activation and proliferation. Dendritic cells (DCs) are considered the most important antigen-presenting cells (APCs) for CD8+T cells, but DCs lose APC function when infected with Friend virus (FV), a model retrovirus of mice. Interestingly, B cells were better able to stimulate CD8+T cell responses when they were infected with FV. We also found that the activation status of B cells under homeostatic conditions was potently modulated by regulatory T cells. This study illustrates an important link between B cell and T cell responses and illustrates an additional mechanism by which regulatory T cells suppress critical T cell responses during viral infections.

scholarly journals CD28 interaction with B7 costimulates primary allogeneic proliferative responses and cytotoxicity mediated by small, resting T lymphocytes.

1992 ◽  
Vol 175 (2) ◽  
pp. 353-360 ◽  
Author(s):  
M Azuma ◽  
M Cayabyab ◽  
D Buck ◽  
J H Phillips ◽  
L L Lanier
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Proliferative Response ◽  
Cell Activation ◽  
B Cell Activation ◽  
Rapid Responses ◽  
Cell Clones

Engagement of the CD3/T cell antigen receptor complex on small, resting T cells is insufficient to trigger cell-mediated cytotoxicity or to induce a proliferative response. In the present study, we have used genetic transfection to demonstrate that interaction of the B7-BB1 B cell activation antigen with the CD28 T cell differentiation antigen costimulates cell-mediated cytotoxicity and proliferation initiated by either anti-CD2 or anti-CD3 monoclonal antibody (mAb). Moreover, a B7-negative Burkitt's lymphoma cell line that fails to stimulate an allogeneic mixed lymphocyte response is rendered a potent stimulator after transfection with B7. The mixed leukocyte reaction proliferative response against the B7 transfectant is inhibited by either anti-CD28 or B7 mAb. We also demonstrate that freshly isolated small, resting human T cells can mediate anti-CD3 or anti-CD2 mAb-redirected cytotoxicity against a murine Fc receptor-bearing mastocytoma transfected with human B7. These preexisting cytotoxic T lymphocytes in peripheral blood are present in both the CD4 and CD8 subsets, but are preferentially within the CD45RO+ "memory" population. While small, resting T cells apparently require costimulation by CD28/B7 interactions, this requirement is lost after T cell activation. Anti-CD3 initiates a cytotoxic response mediated by in vitro cultured T cell clones in the absence of B7 ligand. The existence of functional cytolytic T cells in the small, resting T cell population may be advantageous in facilitating rapid responses to immune challenge.

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