High levels of Fas ligand and MHC class II in the absence of CD80 or CD86 expression and a decreased CD4+ T cell Infiltration, enables murine skin tumours to progress

AbstractMHC class II (MHCII) expression is usually restricted to antigen presenting cells, but can be expressed by cancer cells. We examined the effect of cancer cell-intrinsic MHC class II (csMHCII) expression in lung adenocarcinoma on T cell recruitment to tumors and response to anti-PD-1 therapy. The functional significance of altering csMHCII expression was explored using two orthotopic immunocompetent murine models of non-small cell lung cancer: CMT167 (CMT) and Lewis Lung Carcinoma (LLC). We previously showed that CMT167 tumors are eradicated by anti-PD1 therapy, while LLC tumors are resistant. RNA-seq analysis of cancer cells recovered from tumors revealed that csMHCII correlated with response to anti-PD1 therapy, with immunotherapy-sensitive CMT167 cells being csMHCII positive, while resistant LLC cells were csMHCII negative. To test the functional effects of csMHCII, MHCII expression was altered on the cancer cells through loss- and gain-of-function of CIITA, a master regulator of the MHCII pathway. Loss of CIITA in CMT167 decreased csMHCII, and converted tumors from anti-PD-1-sensitive to anti-PD-1-resistant. This was associated with decreased T cell infiltration, lower levels of Th1 cytokines, increased B cell number and decreased macrophage recruitment. Conversely, overexpression of CIITA in LLC cells resulted in csMHCII in vitro and in vivo. Enforced expression of CIITA increased T cell infiltration and sensitized tumors to anti-PD-1 therapy. csMHCII expression was also examined in a subset of surgically resected human lung adenocarcinomas by multispectral imaging, provided a survival benefit and positively correlated with T cell infiltration. These studies demonstrate a functional role for csMHCII in regulating T cell infiltration and sensitivity to anti-PD-1.

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MHC class II antigen expression and T-cell infiltration in the demyelinating CNS and PNS of the twitcher mouse

Brain Research ◽

10.1016/0006-8993(93)91058-z ◽

1993 ◽

Vol 625 (2) ◽

pp. 186-196 ◽

Cited By ~ 30

Author(s):

Masaki Ohno ◽

Atsushi Komiyama ◽

Parthena M. Martin ◽

Kinuko Suzuki

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

Antigen Expression ◽

Class Ii ◽

Cell Infiltration ◽

Twitcher Mouse ◽

T Cell Infiltration ◽

Class Ii Antigen ◽

Mhc Class Ii Antigen

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Faculty Opinions recommendation of Cutting edge: Conditional MHC class II expression reveals a limited role for B cell antigen presentation in primary and secondary CD4 T cell responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718020496.793480946 ◽

2013 ◽

Author(s):

Tim Manser

Keyword(s):

T Cell ◽

B Cell ◽

Antigen Presentation ◽

Mhc Class Ii ◽

T Cell Responses ◽

Class Ii ◽

Cutting Edge ◽

Cd4 T Cell ◽

Cell Antigen ◽

Cell Responses

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Identification of a CD4+ T cell-stimulating antigen of pathogenic bacteria by expression cloning.

Journal of Experimental Medicine ◽

10.1084/jem.182.6.1751 ◽

1995 ◽

Vol 182 (6) ◽

pp. 1751-1757 ◽

Cited By ~ 49

Author(s):

S Sanderson ◽

D J Campbell ◽

N Shastri

Keyword(s):

T Cells ◽

Listeria Monocytogenes ◽

T Cell ◽

Mhc Class Ii ◽

T Cell Activation ◽

Pathogenic Bacteria ◽

Genomic Library ◽

Class Ii ◽

Cd4 T Cell ◽

Expression Cloning

Identifying the immunogenic proteins that elicit pathogen-specific T cell responses is key to rational vaccine design. While several approaches have succeeded in identifying major histocompatibility complex (MHC) class I bound peptides that stimulate CD8+ T cells, these approaches have been difficult to extend to peptides presented by MHC class II molecules that stimulate CD4+ T cells. We describe here a novel strategy for identifying CD4+ T cell-stimulating antigen genes. Using Listeria monocytogenes-specific, lacZ-inducible T cells as single-cell probes, we screened a Listeria monocytogenes genomic library as recombinant Escherichia coli that were fed to macrophages. The antigen gene was isolated from the E. coli clone that, when ingested by the macrophages, allowed generation of the appropriate peptide/MHC class II complex and T cell activation. We show that the antigenic peptide is derived from a previously unknown listeria gene product with characteristics of a membrane-bound protein.

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Abstract 760: Heme Oxygenase-1 expression in Dendritic Cells determines the Outcome of Transplantation Arteriosclerosis

Circulation ◽

10.1161/circ.116.suppl_16.ii_146 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Annemarie Noordeloos ◽

Elza van Deel ◽

Denise Hermes ◽

Maarten L Simoons ◽

Dirk J Duncker ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Heme Oxygenase ◽

T Cell Activation ◽

Neointimal Hyperplasia ◽

Cd4 T Cell ◽

Cell Infiltration ◽

Heme Oxygenase 1 ◽

T Cell Infiltration ◽

Mhcii Expression

Introduction: Although expression of heme oxygenase-1 (HO1) attenuates transplantation arteriosclerosis, the mechanism by which HO1 exerts its protective effect remains unclear. We studied the effect of HO1-deficient vs. wildtype (WT) dendritic cells (DCs) on the T-cell priming response and outcome in a murine transplant arteriosclerosis model. Methods: At day 0 C57bl6 mice received either WT (n=6) or HO1-knockout DCs (n=6) pre-sensitized with Balb/c splenocytes lysate to accelerate the development of arteriosclerosis. At day 10 an aorta segment from Balb/c mice was transplanted into the carotid artery position of C57Bl6 mice.14 days after transplantation allografts were excised and processed for immunohistochemical analysis. Results: HO1-deficient DCs significantly increased neointimal hyperplasia as compared to WT DCs (116995 vs. 46114μm 2 P<0.05) and incidence of intima formation (83 vs. 50% in WT DC). HO1 deficient DCs also increased medial thickeness (15936 vs.12034 μm 2 P<0.05) and intimal VSMCs content (76 vs. 46% P<0.05) and resulted in more prominent medial cell infiltration (461μm 2 vs. 232μm 2 P<0.05). Although HO1 deficient and WT DCs could be detected in allografts, HO1-nullizygous DCs induced an increase in CD4+ T-cell infiltration (9.5 vs. 0.1% in WT P<0.05) concomitant to a decrease of CD8+ T cell infiltration (8 vs.14%, P<0.05). In line with these observations Affymetrix microarray analysis confirmed that HO1 deletion in DCs was associated with a significant downregulation of MHCII-H2A expression (associated with CD4+T-cell activation) and induction of inhibitors of MHCII expression (including IK protein) whereas MHC I expression remained unchanged. Conclusions: HO1 expression in dendritic cells increases vascular cell infiltration with a higher CD8+/CD4+ T-cell ratio by stabilizing MHCII expression in vascular allografts resulting in inhibition of neointima formation and hence improved allograft survival.

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H2-M and H2-O as Targeting Vehicles for the MHC Class II Processing Compartment Promote Antigen-Specific CD4+ T Cell Activation

Vaccines ◽

10.3390/vaccines9101053 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1053

Author(s):

Lucia Lapazio ◽

Monika Braun ◽

Kaj Grandien

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

T Cell Activation ◽

Cell Activation ◽

Class Ii ◽

Cd4 T Cell ◽

Antigen Presentation Pathway ◽

Presentation Pathway ◽

Class Ii Antigen ◽

Mhc Class Ii Antigen

CD8 and CD4 T cell activation are both required for a strong and long-lasting T cell immune response. Endogenously expressed proteins are readily processed by the MHC class I antigen presentation pathway, enabling activation of CD8+ T cells. However, the MHC class II antigen presentation pathway, necessary for CD4+ T cell activation, is generally not sufficiently accessible to endogenously expressed proteins, limiting the efficiency of mRNA- or DNA-based vaccines. In the current study, we have evaluated the feasibility of using antigen sequences fused to sequences derived from the H2-M and H2-O proteins, two complexes known to participate in MHC class II antigen processing, for the enhancement of CD4 T-cell activation. We analyzed T cell activation after genetic immunization with mRNA-encoding fusion proteins with the model antigen ovalbumin and sequences derived from H2-M or H2-O. Our results show that H2-M- or H2-O-derived sequences robustly improve antigen-specific CD4 T-cell activation when fused to the antigen of interest and suggest that the approach could be used to improve the efficiency of mRNA- or DNA-based vaccines.

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An Alternate Pathway for CD4 T Cell Development: Thymocyte-Expressed MHC Class II Selects a Distinct T Cell Population

Immunity ◽

10.1016/j.immuni.2005.09.002 ◽

2005 ◽

Vol 23 (4) ◽

pp. 375-386 ◽

Cited By ~ 91

Author(s):

Wei Li ◽

Moon-Gyo Kim ◽

Tania S. Gourley ◽

Brian P. McCarthy ◽

Derek B. Sant’Angelo ◽

...

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

Cell Population ◽

T Cell Development ◽

Class Ii ◽

Cell Development ◽

Cd4 T Cell ◽

Alternate Pathway

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Both Stat5a and Stat5b are required for antigen-induced eosinophil and T-cell recruitment into the tissue

Blood ◽

10.1182/blood.v95.4.1370.004k29_1370_1377 ◽

2000 ◽

Vol 95 (4) ◽

pp. 1370-1377 ◽

Cited By ~ 63

Author(s):

Shin-ichiro Kagami ◽

Hiroshi Nakajima ◽

Kotaro Kumano ◽

Kotaro Suzuki ◽

Akira Suto ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Specific Ige ◽

Cd4 T Cell ◽

Cell Infiltration ◽

Cell Recruitment ◽

Eosinophil Recruitment ◽

Airway Eosinophilia ◽

T Cell Infiltration

Antigen-induced eosinophil recruitment into the airways of sensitized mice is mediated by CD4+ T cells and their cytokines, especially IL-5. In this study, we found that the antigen-induced airway eosinophilia was diminished in Stat5a-deficient (Stat5a−/−) mice and Stat5b-deficient (Stat5b−/−) mice. We also found that antigen-induced CD4+ T-cell infiltration and IL-5 production in the airways were diminished in Stat5a−/− mice and Stat5b−/− mice. Moreover, antigen-induced proliferation of splenocytes was diminished in Stat5a−/− mice and Stat5b−/− mice, suggesting that the generation of antigen-primed T cells may be compromised in Stat5a−/−mice and Stat5b−/− mice and this defect may account for the diminished antigen-induced T-cell infiltration into the airways. Interestingly, IL-4 and IL-5 production from anti-CD3–stimulated splenocytes was diminished in Stat5a−/− mice and Stat5b−/− mice. However, antigen-specific IgE and IgG1 production was diminished in Stat5a−/− mice but not in Stat5b−/− mice, whereas antigen-specific IgG2a production was increased in Stat5a−/− mice, suggesting the enhanced Th1 responses in Stat5a−/− mice. Finally, we found that eosinophilopoiesis induced by the administration of recombinant IL-5 was also diminished in Stat5a−/− mice and Stat5b−/− mice. Together, these results indicate that both Stat5a and Stat5b are essential for induction of antigen-induced eosinophil recruitment into the airways and that the defects in antigen-induced eosinophil recruitment in Stat5a−/− mice and Stat5b−/− mice result from both impaired IL-5 production in the airways and diminished IL-5 responsiveness of eosinophils.

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