scholarly journals H-2 restriction of virus-specific T-cell-mediated effector functions in vivo. II. Adoptive transfer of delayed-type hypersensitivity to murine lymphocytic choriomeningits virus is restriced by the K and D region of H-2.

1976 ◽  
Vol 144 (3) ◽  
pp. 776-787 ◽  
Author(s):  
R M Zinkernagel
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Gamma Globulin ◽  
Effector T Cells ◽  
Delayed Type Hypersensitivity ◽  
T Effector Cells ◽  
Immune Lymphocytes ◽  
D Region

In mice, primary footpad swelling after local infection with lymphocytic choriomeningitis virus (LCMV) and delayed-type hypersensitivity (DTH) adoptively transferred by LCMV immune lymphocytes are T-cell dependent. Nude mice do not develop primary footpad swelling, and T-cell depletion abrogates the capacity to transfer LCMV-specific DTH. Effector T cells involved in eliciting dose-dependent DTH are virus specific in that vaccinia virus-immune lymphocytes could not elicit DTH in LCMV-infected mice. The adoptive transfer of DTH is restricted to H-2K or H-2D compatible donor-recipient combinations. Distinct from the fowl-gamma-globulin DTH model, I-region compatibility is neither necessary nor alone sufficient. Whatever the mechanisms involved in this K- or D-region associated restriction in vivo, it most likely operates at the level of T-cell recognition of "altered self" coded in K or D. T cells associated with the I region (helper T cells and DTH-T cells to fowl-gamma-globulin) are specific for soluble, defined, and inert antigens. T cells associated with the K and D region (T cells cytotoxic in vitro and in vivo for acute LCMV-infected cells, DTH effector T cells, and anti-viral T cells) are specific for infectious, multiplying virus. The fact that T-cell specificity is differentially linked with the I region or with the K and D regions of H-2 may reflect the fundamental biological differences of these antigens. Although it cannot be excluded that separate functional subclasses of T-effector cells could have self-recognizers for different cell surface structures coded in I or K and D, it is more likely that the antigen parameters determine whether T cells are specific for "altered" I or "altered" K- or D-coded structures.

scholarly journals A Novel Role for IL-6 Receptor Classic Signaling: Induction of RORγt+Foxp3+ Tregs with Enhanced Suppressive Capacity

2019 ◽  
Vol 30 (8) ◽  
pp. 1439-1453 ◽  
Author(s):  
Julia Hagenstein ◽  
Simon Melderis ◽  
Anna Nosko ◽  
Matthias T. Warkotsch ◽  
Johannes V. Richter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Th17 Cells ◽  
Inflammatory Diseases ◽  
Double Positive ◽  
T Effector Cells ◽  
Suppressive Capacity

BackgroundNew therapies blocking the IL-6 receptor (IL-6R) have recently become available and are successfully being used to treat inflammatory diseases like arthritis. Whether IL-6 blockers may help patients with kidney inflammation currently remains unknown.MethodsTo learn more about the complex role of CD4+ T cell-intrinsic IL-6R signaling, we induced nephrotoxic nephritis, a mouse model for crescentic GN, in mice lacking T cell–specific IL-6Ra. We used adoptive transfer experiments and studies in reporter mice to analyze immune responses and Treg subpopulations.ResultsLack of IL-6Ra signaling in mouse CD4+ T cells impaired the generation of proinflammatory Th17 cells, but surprisingly did not ameliorate the course of GN. In contrast, renal damage was significantly reduced by restricting IL-6Ra deficiency to T effector cells and excluding Tregs. Detailed studies of Tregs revealed unaltered IL-10 production despite IL-6Ra deficiency. However, in vivo and in vitro, IL-6Ra classic signaling induced RORγt+Foxp3+ double-positive Tregs (biTregs), which carry the trafficking receptor CCR6 and have potent immunoregulatory properties. Indeed, lack of IL-6Ra significantly reduced Treg in vitro suppressive capacity. Finally, adoptive transfer of T cells containing IL-6Ra−/− Tregs resulted in severe aggravation of GN in mice.ConclusionsOur data refine the old paradigm, that IL-6 enhances Th17 responses and suppresses Tregs. We here provide evidence that T cell–intrinsic IL-6Ra classic signaling indeed induces the generation of Th17 cells but at the same time highly immunosuppressive RORγt+ biTregs. These results advocate caution and indicate that IL-6–directed therapies for GN need to be cell-type specific.

Sustained delayed-type hypersensitivity reaction after in vivo priming but successful induction of unresponsiveness after adoptive transfer of CD4+ effector T cells

2008 ◽  
Vol 253 (1-2) ◽  
pp. 110-115 ◽  
Author(s):  
Friderike Blumenthal-Barby ◽  
Arnhild Schrage ◽  
Katharina Eulenburg ◽  
Martin Zeitz ◽  
Alf Hamann ◽  
...  
Keyword(s):  
T Cells ◽  
Hypersensitivity Reaction ◽  
Adoptive Transfer ◽  
Effector T Cells ◽  
Delayed Type Hypersensitivity ◽  
Successful Induction

Engraftment Fitness of Human Central Memory-Derived Effector CD8+ T Cells In Immunodeficient Mice

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1019-1019
Author(s):  
Xiuli Wang ◽  
Berger Carolina ◽  
Stanley R. Riddell ◽  
ChingLam W Wong ◽  
Stephen Forman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Tumor Response ◽  
Memory T Cells ◽  
Effector T Cells ◽  
Caspase Activity ◽  
Effector Cells ◽  
Nog Mice

Abstract Abstract 1019 Development of T cell products that have engineered specificity for CD19 has broad application to adoptive transfer therapy for B-lineage lymphoma and leukemia. Clinical studies have demonstrated the safety and feasibility of T cell transfer as a therapy for patients. But the potency of this strategy has proven challenging, primarily due to issues relating to a lack of persistence of the adoptively transferred cells in patients. The repertoire of memory T cells is heterogeneous with respect to phenotypic, functional, and epigenetic attributes. Memory T cells are divided into sub-populations of 1) effector memory (TEM) cells that distribute to tissue beds and exhibit immediate cytolytic effector functioning, and 2) central memory (TCM) cells that home to lymph nodes based on CD62L/CCR7 expression and are capable of extensive proliferative activity upon re-encountering antigen. Thus the cell-intrinsic programming of distinct memory T cell subtypes, such as TEM and TCM, likely dictate divergent fates of their derived effector cells. To address this important issue, a clear functional dichotomy between TCM- and TEM-derived CD8+ CTLs was recently delineated in a nonhuman primate model, where it was found that virus-specific CD8+ CTL clones derived from TCM, but not TEM precursors, establish persistent and functional memory following adoptive transfer. Here, we extended these studies to human effector T cells using CMV as antigen model system to investigate the engraftment of human CMVpp65-specific CD8+ effector T cells derived in vitro from either sort purified CD45RO+CD62L+ TCM or CD45RO+CD62L- TEM precursors in NOD/Scid IL-2RγCnull (NOG) mice. TCM-derived effector cells (TE(CM)) and TEM-derived effector cells (TE(EM)) were adoptively transferred (i.v) into NOG mice reconstituted with human IL-15 and T cell levels in circulation were evaluated at different time points by FACS. 20% CD8+ TE(CM) and 3% CD8+ TE(EM) were detected on day 14. Then after, engraftment of the CD8+ TE(CM) remained at a steady state of approx 2% of circulating mononuclear cells for 100 days while TE(EM) remained at or below the level of detection, indicating that TE(CM) were superior in their ability to engraft in response to IL-15 as compared to TE(EM) after adoptive transfer (P<0.05). The long-term (100 days) persisting CD8+ TE(CM), harvested from primary recipient mice were found to be capable of engrafting secondary recipients. TcR Vβ analysis of persisting cells demonstrated that CD8+ TE(CM) engraftment was polyclonal, suggesting that homeostatic engraftment fitness is a general feature of these cells. To delineate the mechanism(s) by which TE(CM) exhibit superior in vivo engraftment, TE(CM) and TE(EM) were first labeled with CFSE before in vivo administration. CFSE profiles appear that the TE(EM) proliferated more extensively than TE(CM) early after adoptive transfer as indicated by the percent of cells which diluted CFSE on day 9 (i.e., 80% vs. only 25%, respectively). However, using D2R cleavage as a measure of caspase activity as a surrogate for apoptosis, 5.8% of engrafting TE(CM) were positive for activated caspase activity compared to 31.6% of TE(EM), suggesting that in NOG mice both CD8+ TE(CM) and TE(EM) proliferate in response to IL-15 whereas TE(CM) are intrinsically resistant to caspase activation and apoptosis. We also evaluated the antigen specific responsiveness of engrafted cells. Weekly infusions of irradiated pp65+/A2+ LCL as antigen significantly augmented the levels of circulating CD8+ TE(CM) as compared to no antigen stimulation (P<0.05), whereas CD8+ TE(EM) did not respond to antigen challenge. Moreover, when CMVpp65 specific CD8+ TE(CM) or TE(EM) were infused into CMVpp65+ tumor bearing mice, tumor cells progressed in mice receiving TE(EM) at a rate similar to untreated control mice over a ten day observation period, whereas TE(CM) significantly controlled tumor progression (P<0.05), indicating that CD8+ TE(CM) but not TE(EM) are able to mediate an anti-tumor response. Together these studies confirm that human CD8+ effector T cells derived from TCM precursors are capable of persistence after infusion, can proliferate in in vivo in response to antigen, can mediate an anti-viral or anti tumor response, and are likely the preferred T cells for antigen specific anti-tumor adoptive T cell therapy . Disclosures: No relevant conflicts of interest to declare.

scholarly journals CD8+ T Cell–mediated Injury In Vivo Progresses in the Absence of Effector T Cells

2001 ◽  
Vol 194 (12) ◽  
pp. 1835-1846 ◽  
Author(s):  
Barbara A. Small ◽  
Sarah A. Dressel ◽  
Christopher W. Lawrence ◽  
Donald R. Drake ◽  
Mark H. Stoler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tissue Injury ◽  
Cd8 T Cell ◽  
Effector T Cells ◽  
Type Ii ◽  
Pulmonary Injury ◽  
Alveolar Cells ◽  
Type Ii Alveolar Cells

Tissue injury is a common sequela of acute virus infection localized to a specific organ such as the lung. Tissue injury is an immediate consequence of infection with lytic viruses. It can also result from the direct destruction of infected cells by effector CD8+ T lymphocytes and indirectly through the action of the T cell–derived proinflammatory cytokines and recruited inflammatory cells on infected and uninfected tissue. We have examined CD8+ T cell–mediated pulmonary injury in a transgenic model in which adoptively transferred, virus-specific cytotoxic T lymphocytes (CTLs) produce lethal, progressive pulmonary injury in recipient mice expressing the viral target transgene exclusively in the lungs. We have found that over the 4–5 day course of the development of lethal pulmonary injury, the effector CTLs, while necessary for the induction of injury, are present only transiently (24–48 h) in the lung. We provide evidence that the target of the antiviral CD8+ T cells, the transgene expressing type II alveolar cells, are not immediately destroyed by the effector T cells. Rather, after T cell–target interaction, the type II alveolar cells are stimulated to produce the chemokine monocyte chemoattractant protein 1. These results reinforce the concept that, in vivo, the cellular targets of specific CTLs may participate directly in the development of progressive tissue injury by activating in response to interaction with the T cells and producing proinflammatory mediators without sustained in vivo activation of CD8+ T cell effectors.

scholarly journals Tumor masses support naive T cell infiltration, activation, and differentiation into effectors

2010 ◽  
Vol 207 (8) ◽  
pp. 1791-1804 ◽  
Author(s):  
Elizabeth D. Thompson ◽  
Hilda L. Enriquez ◽  
Yang-Xin Fu ◽  
Victor H. Engelhard
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Cell Activation ◽  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Infiltration

Studies of T cell responses to tumors have focused on the draining lymph node (LN) as the site of activation. We examined the tumor mass as a potential site of activation after adoptive transfer of naive tumor-specific CD8 T cells. Activated CD8 T cells were present in tumors within 24 h of adoptive transfer and proliferation of these cells was also evident 4–5 d later in mice treated with FTY720 to prevent infiltration of cells activated in LNs. To confirm that activation of these T cells occurred in the tumor and not the tumor-draining LNs, we used mice lacking LNs. Activated and proliferating tumor-infiltrating lymphocytes were evident in these mice 24 h and 4 d after naive cell transfer. T cells activated within tumors acquired effector function that was evident both ex vivo and in vivo. Both cross-presenting antigen presenting cells within the tumor and tumor cells directly presenting antigen activated these functional CD8 effectors. We conclude that tumors support the infiltration, activation, and effector differentiation of naive CD8 T cells, despite the presence of immunosuppressive mechanisms. Thus, targeting of T cell activation to tumors may present a tool in the development of cancer immunotherapy.

scholarly journals IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell–mediated rejection of systemic lymphoma in immunodeficient mice

Blood ◽  
2010 ◽  
Vol 115 (17) ◽  
pp. 3508-3519 ◽  
Author(s):  
John C. Markley ◽  
Michel Sadelain
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Memory T Cells ◽  
Tumor Rejection ◽  
Effector Memory ◽  
Transfer Model ◽  
Human T Cell

Abstract The γc-cytokines are critical regulators of immunity and possess both overlapping and distinctive functions. However, comparative studies of their pleiotropic effects on human T cell–mediated tumor rejection are lacking. In a xenogeneic adoptive transfer model, we have compared the therapeutic potency of CD19-specific human primary T cells that constitutively express interleukin-2 (IL-2), IL-7, IL-15, or IL-21. We demonstrate that each cytokine enhanced the eradication of systemic CD19+ B-cell malignancies in nonobese diabetic/severe combined immunodeficient (NOD/SCID)/γcnull mice with markedly different efficacies and through singularly distinct mechanisms. IL-7– and IL-21–transduced T cells were most efficacious in vivo, although their effector functions were not as enhanced as IL-2– and IL-15–transduced T cells. IL-7 best sustained in vitro T-cell accumulation in response to repeated antigenic stimulation, but did not promote long-term T-cell persistence in vivo. Both IL-15 and IL-21 overexpression supported long-term T-cell persistence in treated mice, however, the memory T cells found 100 days after adoptive transfer were phenotypically dissimilar, resembling central memory and effector memory T cells, respectively. These results support the use of γc-cytokines in cancer immunotherapy, and establish that there exists more than 1 human T-cell memory phenotype associated with long-term tumor immunity.

scholarly journals In Vivo Detection of Dendritic Cell Antigen Presentation to CD4+ T Cells

1997 ◽  
Vol 185 (12) ◽  
pp. 2133-2141 ◽  
Author(s):  
Elizabeth Ingulli ◽  
Anna Mondino ◽  
Alexander Khoruts ◽  
Marc K. Jenkins
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Delayed Type Hypersensitivity ◽  
Physical Interaction

Although lymphoid dendritic cells (DC) are thought to play an essential role in T cell activation, the initial physical interaction between antigen-bearing DC and antigen-specific T cells has never been directly observed in vivo under conditions where the specificity of the responding T cells for the relevant antigen could be unambiguously assessed. We used confocal microscopy to track the in vivo location of fluorescent dye-labeled DC and naive TCR transgenic CD4+ T cells specific for an OVA peptide–I-Ad complex after adoptive transfer into syngeneic recipients. DC that were not exposed to the OVA peptide, homed to the paracortical regions of the lymph nodes but did not interact with the OVA peptide-specific T cells. In contrast, the OVA peptide-specific T cells formed large clusters around paracortical DC that were pulsed in vitro with the OVA peptide before injection. Interactions were also observed between paracortical DC of the recipient and OVA peptide-specific T cells after administration of intact OVA. Injection of OVA peptide-pulsed DC caused the specific T cells to produce IL-2 in vivo, proliferate, and differentiate into effector cells capable of causing a delayed-type hypersensitivity reaction. Surprisingly, by 48 h after injection, OVA peptide-pulsed, but not unpulsed DC disappeared from the lymph nodes of mice that contained the transferred TCR transgenic population. These results demonstrate that antigen-bearing DC directly interact with naive antigen-specific T cells within the T cell–rich regions of lymph nodes. This interaction results in T cell activation and disappearance of the DC.

scholarly journals Antibody to the murine type 3 complement receptor inhibits T lymphocyte-dependent recruitment of myelomonocytic cells in vivo.

1989 ◽  
Vol 169 (2) ◽  
pp. 535-548 ◽  
Author(s):  
H Rosen ◽  
G Milon ◽  
S Gordon
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Passive Transfer ◽  
Active Immunization ◽  
Delayed Type Hypersensitivity ◽  
Complement Receptor ◽  
Cell Counts ◽  
Type 3

We have used the delayed-type hypersensitivity (DTH) response to SRBC or tuberculin to examine the role of the murine type 3 complement receptor in T lymphocyte-dependent inflammatory recruitment. Intravenous injection of 5C6, a CR3-specific rat mAb known to impair myelomonocytic adhesion, divided the DTH to SRBC in actively immunized mice into two phases. The early phase, which lasted 24 h, was characterized by maximal oedema and maximal inflammatory recruitment and was 5C6 inhibitable. The later phase was 5C6 resistant and reached a peak 48 h after antigenic challenge and was superimposable on the declining peak seen in control mice. Passive transfer of reactive T cells mixed with antigen was used to examine the myelomonocytic effector arm of the DTH alone. Both passive transfer of cutaneous DTH to SRBC and passive transfer of the largely monocytic T cell-dependent recruitment to tuberculin in the peritoneal cavity were completely abolished by systemic 5C6 treatment. Injection of 5C6-treated donor leukocytes at the site of passive transfer had no effect. Treatment of donor mice with 5C6 at the time of active immunization did not alter their ability to provide reactive T cells for passive transfer. The myelomonocyte-restricted rat mAb 7/4 and the rapidly cleared F(ab')2 fragment of 5C6 showed no inhibition of the DTH. In all cases, inhibition of footpad swelling correlated with histological evidence of inhibition of myelomonocytic cell recruitment. Peritoneal cell counts after local DTH to tuberculin showed complete inhibition of monocyte recruitment. We conclude that CR3 plays a quantitatively important role in T cell-dependent inflammatory recruitment. This is absolute in passive transfer experiments, but only partial after active immunization. Leukocyte CR3 plays a common role in both immunologically specific and nonspecific inflammatory recruitment and provides a target that could possibly be manipulated to therapeutic advantage.

T Cells Genetically Modified to Be CD19-Specific with Improved Potential for Trafficking and Activation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1748-1748
Author(s):  
Zaid Al-Kadhimi ◽  
Lisa Marie Serrano ◽  
Simon Olivares ◽  
Sergio Gonzalez ◽  
Timothy Pfeiffer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cytokine Production ◽  
Genetically Modified ◽  
Cell Receptor ◽  
Effector T Cells ◽  
Concentration Gradients ◽  
Chimeric Immunoreceptor

Abstract The safety and feasibility of adoptive immunotherapy using ex vivo-expanded differentiated human effector T cells that express tumor-specific chimeric receptors are being evaluated in clinical trials. Typically, these T cells are CCR7neg and bear a T-cell receptor of unknown specificity. To improve the therapeutic potential of genetically engineered T cells in general, and CD19-specific T cells in particular, strategies are needed to improve their ability traffic to sites of residual/macroscopic disease where infused T cells can be specifically activated for proliferation, cytokine secretion, and tumor-lysis. To accomplish these goals we have generated a selection process that uses genetically modified T cells, expressing influenza A matrix protein 1 (MP1) or CMV pp65, to act as antigen presenting cells (T-APC) in order to expand autologous viral-specific T cells in vitro and in vivo. The viral-specific effector T cells can then be genetically modified with a CD19-specific chimeric immunoreceptor (CD19R), which recognizes CD19 on malignant B cells, independent of MHC. By using these viral-specific T cells as a platform for the introduction of CD19R, we now demonstrate that bi-specific T cells express the chemokine receptor CCR7, which is implicated in the trafficking of T cells to lymph nodes. We demonstrate that this chemokine receptor functions to directionally chemotax the genetically modified bi-specific T-cells along concentration gradients of CCL19 or CCL21. We further demonstrate that both the endogenous and introduced chimeric immunoreceptor continue to function in CCR7+ bi-specific T cells. Indeed, the bi-specific T cells are capable of augmented cytokine production and proliferation upon docking with both CD19 and MP1 antigens, compared with these same T cells interacting with either CD19 or MP1 alone. This enhanced activation is an explanation for the enhanced in vivo anti-tumor activity demonstrated by bi-specific T-cells when stimulated with MP1+ T-APC in treating CD19+ lymphoma in NOD/scid mice. An advantage of this methodology is that the CCR7+ bi-specific T cells and T-APC can be genetically modified and expanded in compliance with current good manufacturing practice (cGMP) for 2nd generation Phase I/II clinical trials to test their ability to traffic to sites of lymphoma providing potent regional/local T-cell activation. Legend: (A) CCR7+ viral- and CD19-bi-specific T cells migrate along recombinant CCL19 and CCL21 concentration gradients, whereas CCR7neg CD19-specific T cells do not. (B) Stimulation of both introduced chimeric immunoreceptor and endogenous T-cell receptor on CD19- and MP1- bi-specific T-cells, using artificial APC, results in augmented cytokine production. Figure Figure

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