scholarly journals Both a monoclonal antibody and antisera specific for determinants unique to individual cloned helper T cell lines can substitute for antigen and antigen-presenting cells in the activation of T cells.

1983 ◽  
Vol 158 (3) ◽  
pp. 836-856 ◽  
Author(s):  
J Kaye ◽  
S Porcelli ◽  
J Tite ◽  
B Jones ◽  
C A Janeway
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Cell Activation ◽  
T Cell Proliferation ◽  
Accessory Cell ◽  
Helper T Cell ◽  
T Cell Lines ◽  
Antigen Presenting

Two antisera and a monoclonal antibody raised in BALB.K mice against cloned, major histocompatibility complex (MHC)-restricted, antigen-specific helper T cell lines are described. These antibodies are specific for individual cloned T cell lines and are potent inducers of T cell proliferation. The induction of T cell proliferation by these antibodies requires the presence of an adherent accessory cell. There is no H-2 restriction between this accessory cell and the cloned T cell, nor is this antibody-induced proliferation blocked by a monoclonal anti-Fc receptor antibody. The requirement for an accessory cell, however, is eliminated in the presence of an IL-1- or IL-2-rich supernatant. Thus this system allows the analysis of helper T cell activation with only a single cell type present. Anti-T cell sera also induce T cell-dependent B cell proliferation and immunoglobulin secretion. The induction of T cell-dependent B cell activation by these sera does not require H-2-matched T cells and B cells. The specificity of these antibodies and their ability to stimulate cloned helper T cells in the absence of antigen and antigen-presenting cells strongly suggest that these antibodies are directed against antigen and/or Ia recognition sites on the T cell.

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 Expression and functional significance of an additional ligand for CTLA-4

1993 ◽  
Vol 90 (23) ◽  
pp. 11054-11058 ◽  
Author(s):  
D J Lenschow ◽  
G H Su ◽  
L A Zuckerman ◽  
N Nabavi ◽  
C L Jellis ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Costimulatory Molecule ◽  
T Cell Proliferation ◽  
Antigen Presenting

Effective T-cell activation requires antigen/major histocompatibility complex engagement by the T-cell receptor complex in concert with one or more costimulatory molecules. Recent studies have suggested that the B7 molecule, expressed on most antigen presenting cells, functions as a costimulatory molecule through its interaction with CD28 on T cells. Blocking the CD28/B7 interaction with CTLA4Ig inhibits T-cell activation in vitro and induces unresponsiveness. We demonstrate that another molecule(s), termed B7-2, is expressed constitutively on dendritic cells, is differentially regulated on B cells, and costimulates naive T cells responding to alloantigen. B7-2 is up-regulated by lipopolysaccharide in < 6 hr and is maximally expressed on the majority of B cells by 24 hr. In contrast, B7 is detected only on a subset of activated B cells late (48 hr) after stimulation. In addition, Con A directly induces B7-2 but not B7 expression on B cells. Finally, although both anti-B7 monoclonal antibodies and CTLA4Ig blocked T-cell proliferation to antigen-expressing B7 transfectants, only CTLA4Ig had any significant inhibitory effect on T-cell proliferation to antigens expressed on natural antigen presenting cells, such as dendritic cells. Thus, B7 is not the only costimulatory molecule capable of initiating T-cell responses since a second ligand, B7-2, can provide a necessary second signal for T-cell activation.

Expression of B7-H1 in Mantle Cell Lymphoma Leads to Inhibition of T Cell Response to Tumor Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2643-2643
Author(s):  
Lijuan Wang ◽  
Jianfei Qian ◽  
Yong Lu ◽  
Haiyan Li ◽  
Sungyoul Hong ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
T Cell Proliferation ◽  
Target Cells ◽  
Specific Lysis ◽  
Control Shrna ◽  
Mantle Cell ◽  
T Cell Lines

Abstract Abstract 2643 Mantle cell lymphoma (MCL) is a unique subtype of incurable B-cell, non-Hodgkin lymphoma, and its overall survival currently remains only 4–5 years. Management of relapsed or refractory MCL patients is still challenging. Immunotherapy may provide an alternative treatment for patients with MCL. Recent studies demonstrated that PD-1/B7-H1 signaling plays a crucial role in T-cell regulation in various immune responses and is involved in peripheral tolerance, autoimmunity, infection, and antitumor immunity. In the present study, we examined whether B7-H1 plays an important role in immune evasion in MCL. We demonstrated that B7-H1 gene and protein were expressed in most MCL cell lines and primary MCL cells from all patients examined. CD3+ T cells were cultured with irradiated MCL cell lines and primary cells, which were pre-incubated with or without anti-B7-H1 monoclonal antibody or control antibody. The presence of anti-B7-H1 blocking antibody, but not control antibody, increased CD3+ T cell proliferation. We confirmed the effect of B7-H1 in suppression of T cell proliferation by knockdown of B7-H1 gene expression using B7-H1 specific and non-specific control shRNA lentiviral particles. Upon transfection, the B7-H1-specific shRNA reduced both B7-H1 gene and surface protein expression, while the control shRNA did not. The B7-H1 specific shRNA, but not control shRNA, augmented CD3+ T cell proliferation. To address whether B7-H1 contributed to the suppression of host antitumor immunity in MCL, allogeneic CD3+ T cells isolated from normal donors were cocultured with irradiated MCL cell line SP53, control shRNA SP53 (SP53-ctl), or B7-H1 targeted shRNA SP53 (SP53-kd), respectively. After 7 days of coculture, CD3+ T cells were harvested and restimulated with newly irradiated SP53, SP53-ctl or SP53-kd cells. After at least 3 repeated cycles of in vitro restimulation, three cytotoxic T lymphocyte (CTL) lines were generated, and named CTL-SP53, CTL-SP53-ctl and CTL-SP53-kd. CTL-SP53-kd showed increased killing of target cells as compared with CTL-SP53 (P <.01) or CTL-SP53-ctl (P <.01). We further showed that B7-H1 targeted shRNA MCL cell line (SP53-kd cells) displayed more specific lysis than SP53 (P <.01) or SP53-trl (P <.01). When SP53 cells were pre-incubated with a blocking anti-B7-H1 monoclonal antibody, it also showed more specific lysis as compared to the control antibody pre-treated cells. In these experiments, purified autologous blood B cells and PBMCs were used as target cells to demonstrate whether T cell lines were cytolytic to normal cells. The results showed that the three CTL cell lines did not kill B cells or PBMCs. Intracellular cytokine staining and ELISA assay demonstrated that T-cell lines express IFN-γ, but not IL-4, IL-6, IL-10 or IL-17, and were thus type I T cells. Moreover, T cell lines stimulated by SP53-kd cells express more IFN-γ than SP53 and SP53-ctl. The T cells also expressed CD45RO, CD28, CD44, but not CD45RA, CD27 or CD62L, indicating that they were memory effector cells. In conclusion, B7-H1 expression may be involved in immune evasion mechanism of MCL. Therefore, B7-H1 may be a promising target for immunotherapy in MCL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals T cell growth and differentiation induced by interleukin-HP1/IL-6, the murine hybridoma/plasmacytoma growth factor.

1988 ◽  
Vol 167 (4) ◽  
pp. 1417-1427 ◽  
Author(s):  
C Uyttenhove ◽  
P G Coulie ◽  
J Van Snick
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
Cell Lines ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Accessory Cell ◽  
Cell Growth And Differentiation ◽  
T Cell Lines

Interleukin-HP1 (HP1)/IL-6 is a 25-30-kD protein produced by macrophages, fibroblasts, and certain T cell lines. It was originally identified as a mouse growth factor for B cell hybridomas and plasmacytomas, and was recently shown to stimulate growth and differentiation of normal B cells. Here we demonstrate that, in the presence of lectins or anti-T cell receptor antibodies, HP1/IL-6 has a growth factor activity equivalent to that of IL-2 for mature thymic and peripheral T cells of both the L3T4+ and Lyt-2+ subsets. Contrary to IL-2 and IL-4, HP1/IL-6 was, however, not capable of supporting the growth of established T cell lines. In addition to its effects on T cell proliferation, HP1/IL-6 also enhanced the differentiation of mouse cytolytic T cell precursors in primary allogeneic mixed lymphocyte cultures. Fractionation of responding cell populations indicated that HP1/IL-6 was capable of restoring the response of accessory cell-depleted T cells to Con A. This observation suggests that the production of HP1/IL-6 by macrophages could, at least partly, explain their role in polyclonal T cell activation.

scholarly journals Costimulation by B7 Modulates Specificity of Cytotoxic T Lymphocytes: A Missing Link That Explains Some Bystander T Cell Activation

1997 ◽  
Vol 186 (10) ◽  
pp. 1787-1791 ◽  
Author(s):  
Pan Zheng ◽  
Yang Liu
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Proliferation ◽  
Target Cells ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation

It has been proposed that some bystander T cell activation may in fact be due to T cell antigen receptor (TCR) cross-reactivity that is too low to be detected by the effector cytotoxic T lymphocyte (CTL). However, this hypothesis is not supported by direct evidence since no TCR ligand is known to induce T cell proliferation and differentiation without being recognized by the effector CTL. Here we report that transgenic T cells expressing a T cell receptor to influenza virus A/NT/68 nucleoprotein (NP) 366-374:Db complexes clonally expand and become effector CTLs in response to homologous peptides from either A/PR8/34 (H1N1), A/AA/60 (H2N2), or A/NT/68 (H3N2). However, the effector T cells induced by each of the three peptides kill target cells pulsed with NP peptides from the H3N2 and H2N2 viruses, but not from the H1N1 virus. Thus, NP366–374 from influenza virus H1N1 is the first TCR ligand that can induce T cell proliferation and differentiation without being recognized by CTLs. Since induction of T cell proliferation was mediated by antigen-presenting cells that express costimulatory molecules such as B7, we investigated if cytolysis of H1N1 NP peptide–pulsed targets can be restored by expressing B7-1 on the target cells. Our results revealed that this is the case. These data demonstrated that costimulatory molecule B7 modulates antigen specificity of CTLs, and provides a missing link that explains some of the bystander T cell activation.

scholarly journals Siplizumab, an Anti-CD2 Monoclonal Antibody, Induces a Unique Set of Immune Modulatory Effects Compared to Alemtuzumab and Rabbit Anti-Thymocyte Globulin In Vitro

2020 ◽  
Vol 11 ◽  
Author(s):  
Christian Binder ◽  
Felix Sellberg ◽  
Filip Cvetkovski ◽  
Erik Berglund ◽  
David Berglund
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mixed Lymphocyte Reaction ◽  
T Cell Proliferation ◽  
Allogeneic Mixed Lymphocyte Reaction ◽  
Dependent Cell

Antibodies are commonly used in organ transplant induction therapy and to treat autoimmune disorders. The effects of some biologics on the human immune system remain incompletely characterized and a deeper understanding of their mechanisms of action may provide useful insights for their clinical application. The goal of this study was to contrast the mechanistic properties of siplizumab with Alemtuzumab and rabbit Anti-Thymocyte Globulin (rATG). Mechanistic assay systems investigating antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell phagocytosis and complement-dependent cytotoxicity were used to characterize siplizumab. Further, functional effects of siplizumab, Alemtuzumab, and rATG were investigated in allogeneic mixed lymphocyte reaction. Changes in T cell activation, T cell proliferation and frequency of naïve T cells, memory T cells and regulatory T cells induced by siplizumab, Alemtuzumab and rATG in allogeneic mixed lymphocyte reaction were assessed via flow cytometry. Siplizumab depleted T cells, decreased T cell activation, inhibited T cell proliferation and enriched naïve and bona fide regulatory T cells. Neither Alemtuzumab nor rATG induced the same combination of functional effects. The results presented in this study should be used for further in vitro and in vivo investigations that guide the clinical use of immune modulatory biologics.

scholarly journals Activation Outcomes Induced in Naïve CD8 T-Cells by Macrophages Primed via “Phagocytic” and Nonphagocytic Pathways

2008 ◽  
Vol 19 (2) ◽  
pp. 701-710 ◽  
Author(s):  
Isabel María Olazabal ◽  
Noa Beatriz Martín-Cofreces ◽  
María Mittelbrunn ◽  
Gloria Martínez del Hoyo ◽  
Balbino Alarcón ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
T Cell Proliferation ◽  
Microtubule Organizing Center ◽  
Antigen Uptake ◽  
Soluble Peptide

The array of phagocytic receptors expressed by macrophages make them very efficient at pathogen clearance, and the phagocytic process links innate with adaptive immunity. Primary macrophages modulate antigen cross-presentation and T-cell activation. We assessed ex vivo the putative role of different phagocytic receptors in immune synapse formation with CD8 naïve T-cells from OT-I transgenic mice and compared this with the administration of antigen as a soluble peptide. Macrophages that have phagocytosed antigen induce T-cell microtubule-organizing center and F-actin cytoskeleton relocalization to the contact site, as well as the recruitment of proximal T-cell receptor signals such as activated Vav1 and PKCθ. At the same doses of loaded antigen (1 μM), “phagocytic” macrophages were more efficient than peptide-antigen–loaded macrophages at forming productive immune synapses with T-cells, as indicated by active T-cell TCR/CD3 conformation, LAT phosphorylation, IL-2 production, and T-cell proliferation. Similar T-cell proliferation efficiency was obtained when low doses of soluble peptide (3–30 nM) were loaded on macrophages. These results suggest that the pathway used for antigen uptake may modulate the antigen density presented on MHC-I, resulting in different signals induced in naïve CD8 T-cells, leading either to CD8 T-cell activation or anergy.

scholarly journals Human T cell activation. II. A new activation pathway used by a major T cell population via a disulfide-bonded dimer of a 44 kilodalton polypeptide (9.3 antigen).

1985 ◽  
Vol 161 (6) ◽  
pp. 1513-1524 ◽  
Author(s):  
T Hara ◽  
S M Fu ◽  
J A Hansen
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Receptor Expression ◽  
T Cell Proliferation ◽  
Activation Pathway

In previous studies (17-21), monoclonal antibody (mAb) 9.3 has been shown to react with a major population of human T cells, which include T4+ helper/inducer T cells and T8+ cytotoxic T cells. In this investigation, mAb 9.3 was shown to precipitate a disulfide-bonded dimer of a 44 kD polypeptide. Comodulation experiments showed that this molecule is not linked to T3/Ti or T11 antigens. mAb 9.3 was capable of inducing T cell proliferation in the presence of 12-o-tetradecanoyl phorbol-13-acetate (TPA). This effect was monocyte-independent. T cell activation with mAb 9.3 and TPA was associated with increases in interleukin 2(IL-2) receptor expression and IL-2 secretion. mAb 9.3 did not activate T cells, even with the addition of IL-1 or IL-2. Modulation of the T3 complex did not abolish mAb 9.3-induced T cell proliferation in the presence of TPA. These results suggest that the 9.3 antigen may serve as a receptor for an activation pathway restricted to a T cell subset.

scholarly journals Allergen-Induced C5a/C5aR1 Axis Activation in Pulmonary CD11b+ cDCs Promotes Pulmonary Tolerance through Downregulation of CD40

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 300 ◽  
Author(s):  
Konstantina Antoniou ◽  
Fanny Ender ◽  
Tillman Vollbrandt ◽  
Yves Laumonnier ◽  
Franziska Rathmann ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
T Cell Proliferation ◽  
C5a Receptor ◽  
The Impact

Activation of the C5/C5a/C5a receptor 1 (C5aR1) axis during allergen sensitization protects from maladaptive T cell activation. To explore the underlying regulatory mechanisms, we analyzed the impact of C5aR1 activation on pulmonary CD11b+ conventional dendritic cells (cDCs) in the context of house-dust-mite (HDM) exposure. BALB/c mice were intratracheally immunized with an HDM/ovalbumin (OVA) mixture. After 24 h, we detected two CD11b+ cDC populations that could be distinguished on the basis of C5aR1 expression. C5aR1− but not C5aR1+ cDCs strongly induced T cell proliferation of OVA-reactive transgenic CD4+ T cells after re-exposure to antigen in vitro. C5aR1− cDCs expressed higher levels of MHC-II and CD40 than their C5aR1+ counterparts, which correlated directly with a higher frequency of interactions with cognate CD4+ T cells. Priming of OVA-specific T cells by C5aR1+ cDCs could be markedly increased by in vitro blockade of C5aR1 and this was associated with increased CD40 expression. Simultaneous blockade of C5aR1 and CD40L on C5aR1+ cDCs decreased T cell proliferation. Finally, pulsing with OVA-induced C5 production and its cleavage into C5a by both populations of CD11b+ cDCs. Thus, we propose a model in which allergen-induced autocrine C5a generation and subsequent C5aR1 activation in pulmonary CD11b+ cDCs promotes tolerance towards aeroallergens through downregulation of CD40.

Sirolimus and GvHD Control: the Rhesus Macaque GvHD Model Reveals That Sirolimus Preferentially Inhibits T Cell Proliferation While Permitting Breakthrough T cell Activation After MHC-Mismatched Hematopoietic Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2549-2549
Author(s):  
Karnail Singh ◽  
Swetha Srinivasan ◽  
Angela Panoskaltsis-Mortari ◽  
Sharon Sen ◽  
Kelly Hamby ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Granzyme B ◽  
T Cell Proliferation ◽  
Ki 67 ◽  
Post Transplant

Abstract Abstract 2549 Introduction: Given the emerging importance of sirolimus as a therapuetic for graft-versus host disease (GvHD), it is critical to rigorously define the mechanisms by which this agent impacts T cell immunity after hematopoietic stem cell transplantation (HSCT). Therefore, we have used our novel rhesus macaque model of haploidentical HSCT and GVHD to probe the mechanisms of sirolimus-mediated GvHD prevention when given as a monotherapy. The insights gained from this study will facilitate the rational design of sirolimus-containing combinatorial therapies to maximize immunosuppressive efficacy. Methods: Transplant recipients were prepared with 8Gy total body irradiation and were then infused with MHC-mismatched donor leukopheresis products(n=3, avg. 6.5×108 TNC/kg, 3.4×107 total T cells/kg). Recipients received sirolimus monotherapy (serum troughs 5–15 ng/mL) alone as post-transplant immunosuppresson. Clinical GvHD was monitored according to our standard primate GvHD scoring system and flow cytometric analysis was performed to determine the immune phenotype of sirolimus-treated recipients compared to a cohort of recipients (n= 3) that were given no GvHD immunoprophylaxis. Results: Sirolimus modestly prolonged survival after MHC-mismatched HSCT compared to no immunosuppression (>19 days versus 6.5 days in the untreated cohort, with GvHD confirmed histopathologically at the time of necropsy). We found that sirolimus significantly inhibited lymphocyte proliferation in transplant recipients: The ALC remained suppressed post-transplant (eg ALC of 0.46 × 106/mL on day 15 post-transplant versus 4.3 × 106/mL pre-transplant, with recovery of other leukocytes: WBC=5.1 × 106/mL, ANC=2.6 × 106/mL). These results suggest that sirolimus can have a profound impact on lymphocyte proliferation, inhibiting GvHD-associated lymphocyte expansion by as much as 200–300-fold compared to untreated controls. Sirolimus had a similar impact on CD4+ and CD8+ subpopulation expansion. Thus, while CD4+ T cells and CD8+ T cells expanded by as much as 300-fold and 2000-fold, respectively, without sirolimus, the expansion of these cells was significantly blunted with sirolimus, with maximal expansion of CD4+ and CD8+ T cells being 4- and 3.6-fold, respectively compared to the post-transplant nadir. Sirolimus-treated recipients also better controlled the upregulation of the proliferation marker Ki-67 on CD4+ or CD8+ T cells. Thus, while untreated recipients upregulated Ki-67 expression by as much as 10-fold after engraftment, (with >80-98% T cells expressing high levels of Ki-67 post-transplant versus 5–10% pre-transplant) sirolimus-treated recipients better controlled Ki-67 expression (17-40% Ki-67-high CD4+ and CD8+ T cells post-transplant). While the impact of sirolimus on T cell proliferation was profound, it failed to completely inhibit activation of T cells, as measured by both Granzyme B and CD127 expression. Thus, when effector CD4+ and CD8+ T cell cytotoxic potential was measured by determining expression levels of granzyme B, we found that sirolimus could not downregulate this key component of immune function and GvHD-mediated target organ damage: Granzyme B expression in both CD4+ and CD8+ CD28-/CD95+ effector T cells was unchanged despite sirolimus monotherapy. Down-regulation of CD127 expression, which identifies activated CD8+ T cells in both humans and rhesus macaques, also demonstrated resistance to sirolimus treatment. Thus, while a cohort of recipients that were treated with combined costimulation blockade and sirolimus maintained stable CD127 levels post-transplant, and untreated animals demonstrated total loss of CD127, up to 60% of CD8+ T cells in sirolimus-treated recipients down-regulated CD127, consistent with breakthrough activation of these cells despite mTOR inhibition. Discussion: These results indicate that while the predominant effect of sirolimus during GvHD prophylaxis is its striking ability to inhibit T cell proliferation, sirolimus-based immunosuppression spares some cellular signaling pathways which control T cell activation. These results imply that therapies that are combined with sirolimus during multimodal GvHD prophylaxis should be directed at inhibiting T cell activation rather than proliferation, in order to target non-redundant pathways of alloimmune activation during GvHD control. Disclosures: No relevant conflicts of interest to declare.

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