scholarly journals Oligodendrocyte Precursor Cells Are Co-Opted by the Immune System to Cross-Present Antigen and Mediate Cytotoxicity

2018 ◽  
Author(s):  
Leslie Kirby ◽  
Jing Jin ◽  
Jaime Gonzalez Cardona ◽  
Matthew D. Smith ◽  
Kyle A. Martin ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Mhc Class I ◽  
Antigen Processing ◽  
Precursor Cells ◽  
Class I ◽  
Autoimmune Response ◽  
Oligodendrocyte Precursor Cells ◽  
Oligodendrocyte Precursor

AbstractOligodendrocyte precursor cells (OPCs) are abundant in the adult CNS and can be recruited to form new oligodendrocytes and myelin in response to injury or disease. However, in multiple sclerosis (MS), oligodendrocyte regeneration and remyelination are often incomplete, suggesting that recruitment and maturation of OPCs is impaired. MS and the rodent model experimental autoimmune encephalomyelitis (EAE) are characterized by infiltration of activated T-cells into the CNS. To investigate the mechanisms by which this neuroinflammatory process influences OPC mobilization, we performed in vivo fate tracing in an inflammatory demyelinating animal model. Results of our studies showed that the OPC differentiation and myelin production are inhibited by either adoptive transfer of CNS infiltrating cytokine producing effector T-cells or CNS production of interferon gamma (IFNγ), using an astrocyte specific IFNγ transgene model. In both systems, IFNγ changes the profile of OPCs by inducing functional expression of the immunoproteasome and upregulation of MHC class I. OPCs exposed to IFNγ are shown to cross present exogenous antigen to cytotoxic CD8 T-cells, which then produce proteases and FasL that results in subsequent caspase 3/7 activation and OPC death, both in vitro and in vivo. Cross presentation by OPCs is dependent on the cytosolic processing pathway and can be inhibited by small molecules targeting MHC class I antigen processing and the immunoproteasome subunits. Finally, the immunoproteasome subunit, PSMB8, is shown to be markedly increased on Sox10+ oligodendrocyte lineage cells only in the demyelinated white matter lesions from patients with MS. These findings support the notion that OPCs have multiple functions beyond differentiation into myelinating cells and adapt to their microenvironment by responding to local cues. In MS, OPCs may be co-opted by the immune system to perpetuate the autoimmune response. Strategies aimed at inhibiting the aberrant immune activation pathways in OPCs may allow more efficient remyelination in MS.

CD4 and CD8 TCRαβ Cells Are selected On MHC Expressed On Thymocyte Precursors in OP9-DL1 Cultures.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3670-3670
Author(s):  
Stefanie Van Coppernolle ◽  
Bart Vandekerckhove ◽  
Greet Verstichel ◽  
Imke Velghe ◽  
Tom Taghon ◽  
...  
Keyword(s):  
T Cells ◽  
Positive Selection ◽  
Mhc Class I ◽  
Conflicts Of Interest ◽  
Precursor Cells ◽  
Class I ◽  
Thymic Epithelial Cells ◽  
Cd8 Cells ◽  
Human Cd34

Abstract Abstract 3670 Poster Board III-606 Human CD34+ haematopoietic precursor cells cultured on delta-like-ligand 1 expressing OP9 (OP9-DL1) stromal cells differentiate to T lineage cells. The nature of the T cells generated in these cultures has not been studied in detail. Since these cultures do not contain thymic epithelial cells (TEC) which are the main cell type mediating positive selection in vivo, generation of conventional helper CD4+ and cytotoxic CD8+ TCRαβ cells is not expected. Phenotypically mature CD27+ CD1− TCRγδ as well as TCRαβ cells were generated in OP9-DL1 cultures. CD8 and few mature CD4 single positive (SP) TCRαβ cells were observed. Mature CD8 SP cells consisted of two subpopulations: one expressing mainly CD8αβ and one expressing CD8αα dimers. TCRαβ CD8αα and TCRγδ cells both expressed the IL2Rβ receptor constitutively and proliferated on IL-15, a characteristic of unconventional T cells. CD8αβ+ and CD4+ TCRαβ+ cells were unresponsive to IL-15, but could be expanded upon TCR stimulation as mature CD8αβ+ and CD4+ T cells. These T cells had the characteristics of conventional T cells: CD4+ cells expressed ThPOK, CD40L and high levels of IL-2 and IL-4; CD8+ cells expressed EOMES, RUNX3 and high levels of granzyme, perforin and IFN-γ. Induction of murine or human MHC class I expression on OP9-DL1 cells had no influence on the differentiation of mature CD8+ cells, whereas blocking MHC class I antibodies and CD8 antibodies inhibited generation of mature CD27+ CD8+ SP cells. The presence of dendritic cells was not required for the generation of mature CD4+ or CD8+ T cells. In conclusion, we have demonstrated positive selection of TCRαβ+ cells in the absence of TEC. The data suggest that positive selection is induced by interaction between T precursor cells without requirement for other haematologic or stromal elements. Disclosures: No relevant conflicts of interest to declare.

Histone deacetylase inhibition is cytotoxic to oligodendrocyte precursor cells in vitro and in vivo

2016 ◽  
Vol 54 (1) ◽  
pp. 53-61 ◽  
Author(s):  
Toros A. Dincman ◽  
Jason E. Beare ◽  
Sujata Saraswat Ohri ◽  
Vittorio Gallo ◽  
Michal Hetman ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Precursor Cells ◽  
Oligodendrocyte Precursor Cells ◽  
Histone Deacetylase Inhibition ◽  
Oligodendrocyte Precursor

scholarly journals Efficient Targeting of Protein Antigen to the Dendritic Cell Receptor DEC-205 in the Steady State Leads to Antigen Presentation on Major Histocompatibility Complex Class I Products and Peripheral CD8+ T Cell Tolerance

2002 ◽  
Vol 196 (12) ◽  
pp. 1627-1638 ◽  
Author(s):  
Laura Bonifaz ◽  
David Bonnyay ◽  
Karsten Mahnke ◽  
Miguel Rivera ◽  
Michel C. Nussenzweig ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Steady State ◽  
T Cell ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Class I ◽  
Histocompatibility Complex ◽  
Dc Maturation

To identify endocytic receptors that allow dendritic cells (DCs) to capture and present antigens on major histocompatibility complex (MHC) class I products in vivo, we evaluated DEC-205, which is abundant on DCs in lymphoid tissues. Ovalbumin (OVA) protein, when chemically coupled to monoclonal αDEC-205 antibody, was presented by CD11c+ lymph node DCs, but not by CD11c− cells, to OVA-specific, CD4+ and CD8+ T cells. Receptor-mediated presentation was at least 400 times more efficient than unconjugated OVA and, for MHC class I, the DCs had to express transporter of antigenic peptides (TAP) transporters. When αDEC-205:OVA was injected subcutaneously, OVA protein was identified over a 4–48 h period in DCs, primarily in the lymph nodes draining the injection site. In vivo, the OVA protein was selectively presented by DCs to TCR transgenic CD8+ cells, again at least 400 times more effectively than soluble OVA and in a TAP-dependent fashion. Targeting of αDEC-205:OVA to DCs in the steady state initially induced 4–7 cycles of T cell division, but the T cells were then deleted and the mice became specifically unresponsive to rechallenge with OVA in complete Freund's adjuvant. In contrast, simultaneous delivery of a DC maturation stimulus via CD40, together with αDEC-205:OVA, induced strong immunity. The CD8+ T cells responding in the presence of agonistic αCD40 antibody produced large amounts of interleukin 2 and interferon γ, acquired cytolytic function in vivo, emigrated in large numbers to the lung, and responded vigorously to OVA rechallenge. Therefore, DEC-205 provides an efficient receptor-based mechanism for DCs to process proteins for MHC class I presentation in vivo, leading to tolerance in the steady state and immunity after DC maturation.

scholarly journals Immunotherapy of a murine tumor with interleukin 2. Increased sensitivity after MHC class I gene transfection.

1987 ◽  
Vol 166 (6) ◽  
pp. 1716-1733 ◽  
Author(s):  
J S Weber ◽  
G Jay ◽  
K Tanaka ◽  
S A Rosenberg
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Interleukin 2 ◽  
Class I ◽  
High Dose ◽  
Class I Mhc ◽  
High Doses ◽  
I Gene

We have shown that two weakly immunogenic MCA sarcomas developed in our laboratory that are sensitive to high-dose IL-2 immunotherapy express class I MHC in vivo and in vitro. Two nonimmunogenic MCA sarcomas are relatively insensitive to IL-2 therapy and express minimal or no class I MHC molecules in vivo and in vitro. To study the role of MHC in the therapy of tumors with IL-2, a class I-deficient murine melanoma, B16BL6, was transfected with the Kb class I gene. Expression of class I MHC rendered B16BL6 advanced pulmonary macrometastases sensitive to IL-2 immunotherapy. 3-d micrometastases of CL8-2, a class I transfected clone of B16BL6, were significantly more sensitive to IL-2 therapy than a control nontransfected line. Expression of Iak, a class II MHC molecule, had no effect on IL-2 therapy of transfectant pulmonary micrometastases in F1 mice. By using lymphocyte subset depletion with mAbs directed against Lyt-2, therapy of class I transfectant macrometastases with high-dose IL-2 was shown to involve an Lyt-2 cell. In contrast, regression of micrometastases treated with low-dose IL-2 involved Lyt-2+ cells, but regression mediated by high doses of IL-2 did not. We hypothesize that both LAK and Lyt-2+ T cells effect IL-2-mediated elimination of micrometastases, but only Lyt-2+ T cells are involved in macrometastatic regression. Low doses of IL-2 stimulate Lyt-2+ cells to eliminate class I-expressing micrometastases, but high doses of IL-2 can recruit LAK cells to mediate regression of micrometastases independent of class I expression. Only high-dose IL-2, mediating its effect predominantly via Lyt-2+ cells, is capable of impacting on MHC class I-expressing macrometastases. Macrometastases devoid of class I MHC antigens appear to be resistant to IL-2 therapy.

IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing

Blood ◽  
2012 ◽  
Vol 119 (6) ◽  
pp. 1407-1417 ◽  
Author(s):  
Francesca Spadaro ◽  
Caterina Lapenta ◽  
Simona Donati ◽  
Laura Abalsamo ◽  
Vincenzo Barnaba ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Tumor Development ◽  
Class I ◽  
Cross Presentation ◽  
The Cross ◽  
Human Dendritic Cells

Abstract Cross-presentation allows antigen-presenting cells to present exogenous antigens to CD8+ T cells, playing an essential role in controlling infections and tumor development. IFN-α induces the rapid differentiation of human mono-cytes into dendritic cells, known as IFN-DCs, highly efficient in mediating cross-presentation, as well as the cross-priming of CD8+ T cells. Here, we have investigated the mechanisms underlying the cross-presentation ability of IFN-DCs by studying the intracellular sorting of soluble ovalbumin and nonstructural-3 protein of hepatitis C virus. Our results demonstrate that, independently from the route and mechanism of antigen entry, IFN-DCs are extraordinarily competent in preserving internalized proteins from early degradation and in routing antigens toward the MHC class-I processing pathway, allowing long-lasting, cross-priming capacity. In IFN-DCs, both early and recycling endosomes function as key compartments for the storage of both antigens and MHC-class I molecules and for proteasome- and transporter-associated with Ag processing–dependent auxiliary cross-presentation pathways. Because IFN-DCs closely resemble human DCs naturally occurring in vivo in response to infections and other danger signals, these findings may have important implications for the design of vaccination strategies in neoplastic or chronic infectious diseases.

scholarly journals Constitutive versus Activation-dependent Cross-Presentation of Immune Complexes by CD8+ and CD8− Dendritic Cells In Vivo

2002 ◽  
Vol 196 (6) ◽  
pp. 817-827 ◽  
Author(s):  
Joke M.M. den Haan ◽  
Michael J. Bevan
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Immune Complexes ◽  
Class I ◽  
Cross Presentation ◽  
Deficient Mice ◽  
Mhc Class I Molecules

Murine splenic dendritic cells (DCs) can be divided into two subsets based on CD8α expression, but the specific role of each subset in stimulation of T cells is largely unknown. An important function of DCs is the ability to take up exogenous antigens and cross-present them in the context of major histocompatibility complex (MHC) class I molecules to CD8+ T cells. We previously demonstrated that, when cell-associated ovalbumin (OVA) is injected into mice, only the CD8+ DC subset cross-presents OVA in the context of MHC class I. In contrast to this selectivity with cell-associated antigen, we show here that both DC subsets isolated from mice injected with OVA/anti-OVA immune complexes (OVA-IC) cross-present OVA to CD8+ T cells. The use of immunoglobulin G Fc receptor (FcγR) common γ-chain–deficient mice revealed that the cross-presentation by CD8− DCs depended on the expression of γ-chain–containing activating FcγRs, whereas cross-presentation by CD8+ DCs was not reduced in γ-chain–deficient mice. These results suggest that although CD8+ DCs constitutively cross-present exogenous antigens in the context of MHC class I molecules, CD8− DCs only do so after activation, such as via ligation of FcγRs. Cross-presentation of immune complexes may play an important role in autoimmune diseases and the therapeutic effect of antitumor antibodies.

scholarly journals Qa-2–Dependent Selection of Cd8α/α T Cell Receptor α/β+ Cells in Murine Intestinal Intraepithelial Lymphocytes

2000 ◽  
Vol 192 (10) ◽  
pp. 1521-1528 ◽  
Author(s):  
Gobardhan Das ◽  
Dina S. Gould ◽  
Mathew M. Augustine ◽  
Gladis Fragoso ◽  
Edda Scitto ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Antigen Processing ◽  
Intraepithelial Lymphocytes ◽  
Class I ◽  
Β Cells ◽  
Double Knockout ◽  
Intestinal Intraepithelial Lymphocytes ◽  
Mhc Class I Molecule ◽  
Nonclassical Mhc

Murine intestinal intraepithelial lymphocytes (iIELs) are made up of a heterogeneous mix of T cells with unique phenotypes. Whereas CD8+ T cells in peripheral lymphoid organs use CD8α/β and are selected on MHC class Ia molecules, a majority of iIELs use CD8α/α. Here, we report that the presence of CD8α/α TCR-α/β cells in iIELs is independent of classical MHC class I molecules Kb and Db, as illustrated by their presence in Kb/Db double-knockout mice and in mice lacking a nonclassical MHC class I molecule, CD1d. Most strikingly, their presence is decreased by ∼70% in mice lacking transporter associated with antigen processing (TAP). The TAP-dependent nonclassical MHC class I molecule Qa-2 is strongly implicated in the presence of these cells, as inferred from the low numbers of CD8α/α TCR-α/β T cells in mice deficient in Qa-2 genes. Second, a Qa-2–transgenic mouse made in a Qa-2− strain showed an increase in the numbers of CD8α/α cells among its iIELs. Thus, the presence of CD8α/α TCR-α/β cells in iIELs is mainly dependent on the nonclassical MHC class I molecule Qa-2.

scholarly journals Evidence for involvement of dual-function T cells in rejection of MHC class I disparate skin grafts. Assessment of MHC class I alloantigens as in vivo helper determinants.

1988 ◽  
Vol 168 (1) ◽  
pp. 33-45 ◽  
Author(s):  
A S Rosenberg ◽  
T Mizuochi ◽  
A Singer
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Third Party ◽  
Class I ◽  
Dual Function ◽  
Skin Grafts ◽  
Cellular Mechanisms ◽  
Th Cells ◽  
Skin Allografts

The present study further characterizes the cellular mechanisms involved in the in vivo rejection of MHC class I-disparate skin allografts. Previously, we demonstrated that class I-specific rejection responses could result from collaborations between distinct populations of lymphokine-secreting T helper (Th) and lymphokine-responsive T effector (Teff) cells. In the present study, we have assessed the possibility that class I-specific rejection responses could also result from a second cellular mechanism involving a single population of dual-function Th/Teff cells that would not have any further requirement for cell-cell collaboration. Our experimental strategy was to determine the ability of MHC class I-allospecific T cells, in response to class I allodeterminants expressed on skin grafts, to provide help in vivo for activation of helper-dependent Teff cells. We found that class I anti-Kbm1-allospecific T cells would reject bm1 skin allografts, but would not generate help for the activation of helper-dependent effector cells that were specific for third-party skin allografts (e.g., grafts expressing Kbm6, Qa1a, or H-Y allodeterminants). This failure of anti-Kbm1 T cells to provide help in response to bm1 skin allografts was not due to an inability of lymphokine-secreting anti-Kbm1 Th cells to recognize and respond in vivo to Kbm1 allodeterminants expressed on skin, since lymphokine-secreting anti-Kbm1 Th cells were specifically primed in animals engrafted with bm1 skin allografts. Nor was any evidence found that this failure was due to active suppression of anti-Kbm1 helper activity. Rather, we found that anti-Kbm1 T cells consumed nearly all of the helper factors they secreted. Taken together, these results are most consistent with the in vivo activity of dual-function Th/Teff cells that consume the lymphokines they secrete. Thus, this study demonstrates that MHC class I-disparate skin allografts can be rejected by two mechanisms, depending on the ability of the allospecific Teff cell to secrete helper lymphokines. MHC class I-disparate grafts can be rejected by (a) class I-allospecific Teff cells that are unable to produce lymphokine but are responsive to exogenous T cell help; and (b) class I-allospecific dual-function Th/Teff cells that are able to both produce and consume soluble lymphokine.

scholarly journals Identification of human cancers deficient in antigen processing.

1993 ◽  
Vol 177 (2) ◽  
pp. 265-272 ◽  
Author(s):  
N P Restifo ◽  
F Esquivel ◽  
Y Kawakami ◽  
J W Yewdell ◽  
J J Mulé ◽  
...  
Keyword(s):  
T Cells ◽  
Endoplasmic Reticulum ◽  
Mhc Class I ◽  
Cell Lines ◽  
Antigen Processing ◽  
Human Tumor ◽  
Class I ◽  
Cell Lung Carcinoma ◽  
Mhc Molecules ◽  
Mhc Class I Molecules

Intracellular antigens must be processed before presentation to CD8+ T cells by major histocompatibility complex (MHC) class I molecules. Using a recombinant vaccinia virus (Vac) to transiently express the Kd molecule, we studied the antigen processing efficiency of 26 different human tumor lines. Three cell lines, all human small cell lung carcinoma, consistently failed to process endogenously synthesized proteins for presentation to Kd-restricted, Vac-specific T cells. Pulse-chase experiments showed that MHC class I molecules were not transported by these cell lines from the endoplasmic reticulum to the cell surface. This finding suggested that peptides were not available for binding to nascent MHC molecules in the endoplasmic reticulum. Northern blot analysis of these cells revealed low to nondetectable levels of mRNAs for MHC-encoded proteasome components LMP-7 and LMP-2, as well as the putative peptide transporters TAP-1 and TAP-2. Treatment of cells with interferon gamma enhanced expression of these mRNAs and reversed the observed functional and biochemical deficits. Our findings suggest that downregulation of antigen processing may be one of the strategies used by tumors to escape immune surveillance. Potential therapeutic applications of these findings include enhancing antigen processing at the level of the transcription of MHC-encoded proteasome and transporter genes.

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