Giving CD4+ T cells the slip: viral interference with MHC class II-restricted antigen processing and presentation

Forsyth, Katherine S.; Eisenlohr, Laurence C.

doi:10.1016/j.coi.2016.03.003

Cited by 24 publications

(25 citation statements)

References 71 publications

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“…MHC class II molecules are continuously synthesized in response to MTB infection, during which they are loaded with antigenic peptides in the MHC compartment, thereby priming CD4 ϩ T cells (44). Previously, PE_PGRS47 was found to inhibit MHC class II-restricted antigen presentation by dendritic cells (45).…”

Section: Discussionmentioning

confidence: 99%

“…These findings indicate that the suppression or activation of the MHC-II system by PE/PPE antigens may be the molecular basis of immune surveillance during MTB infection. Focusing on ways to provide an optimal MHC-II-restricted antigen presentation to CD4 ϩ T helper cells may be a crucial parameter for optimal and protective adaptive immune response against TB (44).…”

Section: Discussionmentioning

confidence: 99%

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Mycobacterium tuberculosis PPE60 antigen drives Th1/Th17 responses via Toll-like receptor 2–dependent maturation of dendritic cells

Zhang

Liu

et al. 2018

Journal of Biological Chemistry

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Targeting of (MTB) PE/PPE antigens that induce type 1 helper T cell (Th1) and Th17 responses represents a crucial strategy for the development of tuberculosis (TB) vaccines. However, only a few PE/PPE antigens induce these responses. Here, we sought to determine how the cell wall-associated antigen PPE60 (Rv3478) activates dendritic cell (DC) maturation and T-cell differentiation. We observed that PPE60 induces DC maturation by augmenting the protein expression of cluster of differentiation 80 (CD80) and CD86 and major histocompatibility complex (MHC) class I and MHC class II on the cell surface. PPE60 also stimulated the production of tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-6, IL-12p70, and IL-23p19 but not IL-10. This induction was mediated by Toll-like receptor 2 (TLR2) and followed by activation of p38, c-Jun N-terminal kinase (JNK), and NF-κB signaling. PPE60 enhanced MHC-II expression and promoted antigen processing by DCs in a TLR2-dependent manner. Moreover, PPE60-stimulated DCs directed naïve CD4 T cells to produce IFN-γ, IL-2, and IL-17A, expanding the Th1 and Th17 responses, along with activation of T-bet and RAR-related orphan receptor C (RORγt) but not GATA-3. Moreover, PPE60 activated the NLRP3 inflammasome followed by caspase-1-dependent IL-1β and IL-18 synthesis in DCs. Of note, pharmacological inhibition of NLRP3 activation specifically attenuated IFN-γ and IL-17A secretion into the supernatant from CD4 T cells cocultured with PPE60-activated DCs. These findings indicate that PPE60 induces Th1 and Th17 immune responses by activating DCs in a TLR2-dependent manner, suggesting PPE60's potential for use in MTB vaccine development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis PPE60 antigen drives Th1/Th17 responses via Toll-like receptor 2–dependent maturation of dendritic cells

Zhang

Liu

et al. 2018

Journal of Biological Chemistry

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“…MHC-II molecules continuously expressed in response to infection can load with antigenic peptides in the MHC compartment, and then export to the plasma membrane, where they prime CD4 + T cells (Forsyth and Eisenlohr, 2016). Transcriptional control of MHC-II expression may be a molecular basis of immune surveillance, through which APC functions are regulated by M. tuberculosis protein during infection (Ramachandra et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Recombinant Lipoprotein Rv1016c Derived from Mycobacterium tuberculosis Is a TLR-2 Ligand that Induces Macrophages Apoptosis and Inhibits MHC II Antigen Processing

Zhu

et al. 2016

Front. Cell. Infect. Microbiol.

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TLR2-dependent cellular signaling in Mycobacterium tuberculosis-infected macrophages causes apoptosis and inhibits class II major histocompatibility complex (MHC-II) molecules antigen processing, leading to evasion of surveillance. Mycobacterium tuberculosis (MTB) lipoproteins are an important class of Toll-like receptor (TLR) ligand, and identified as specific components that mediate these effects. In this study, we identified and characterized MTB lipoprotein Rv1016c (lpqT) as a cell wall associated-protein that was exposed on the cell surface and enhanced the survival of recombinants M. smegmatis_Rv1016c under stress conditions. We found that Rv1016c lipoprotein was a novel TLR2 ligand and able to induce macrophage apoptosis in a both dose- and time-dependent manner. Additionally, apoptosis induced by Rv1016c was reserved in THP-1 cells blocked with anti-TLR-2 Abs or in TLR2−/− mouse macrophages, indicating that Rv1016c-induced apoptosis is dependent on TLR2. Moreover, we demonstrated that Rv1016c lipoprotein inhibited IFN-γ-induced MHC-II expression and processing of soluble antigens in a TLR2 dependent manner. Class II transactivator (CIITA) regulates MHC II expression. In this context, Rv1016c lipoprotein diminished IFN-γ-induced expression of CIITA IV through TLR2 and MAPK Signaling. TLR2-dependent apoptosis and inhibition of MHC-II Ag processing induced by Rv1016c during mycobacteria infection may promote the release of residual bacilli from apoptotic cells and decrease recognition by CD4+ T cells. These mechanisms may allow intracellular MTB to evade immune surveillance and maintain chronic infection.

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“…2 MHC II recognition by CD4 1 T cells can also lead to killing of target B cells, contributing to the elimination of infected or transformed cells 3,4 and selecting for the loss of MHC II during viral infection or cancer evolution. 5,6 germline deletion of the conditional H2-Ab1 allele inherited from the Cre 2 -transmitting parent, H2-Ab1 c mice contained only 1 functional conditional allele, inherited from the Cre 2 parent, and therefore expressed reduced levels of MHC II in Cre 2 cells. Mice constitutively lacking all conventional MHC II genes (H2 dlAb1-Ea ), 26 Rag1-deficient (Rag1 2/2 ) mice, 27 and Rag2-deficient (Rag2 2/2 ) mice 28 have been previously described.…”

Section: Introductionmentioning

confidence: 99%

MHC class II cell-autonomously regulates self-renewal and differentiation of normal and malignant B cells

Merkenschlager¹,

Eksmond²,

Danelli³

et al. 2019

Blood

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Best known for presenting antigenic peptides to CD4+ T cells, major histocompatibility complex class II (MHC II) also transmits or may modify intracellular signals. Here, we show that MHC II cell-autonomously regulates the balance between self-renewal and differentiation in B-cell precursors, as well as in malignant B cells. Initiation of MHC II expression early during bone marrow B-cell development limited the occupancy of cycling compartments by promoting differentiation, thus regulating the numerical output of B cells. MHC II deficiency preserved stem cell characteristics in developing pro-B cells in vivo, and ectopic MHC II expression accelerated hematopoietic stem cell differentiation in vitro. Moreover, MHC II expression restrained growth of murine B-cell leukemia cell lines in vitro and in vivo, independently of CD4+ T-cell surveillance. Our results highlight an important cell-intrinsic contribution of MHC II expression to establishing the differentiated B-cell phenotype.

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Giving CD4+ T cells the slip: viral interference with MHC class II-restricted antigen processing and presentation

Cited by 24 publications

References 71 publications

Mycobacterium tuberculosis PPE60 antigen drives Th1/Th17 responses via Toll-like receptor 2–dependent maturation of dendritic cells

Mycobacterium tuberculosis PPE60 antigen drives Th1/Th17 responses via Toll-like receptor 2–dependent maturation of dendritic cells

Recombinant Lipoprotein Rv1016c Derived from Mycobacterium tuberculosis Is a TLR-2 Ligand that Induces Macrophages Apoptosis and Inhibits MHC II Antigen Processing

MHC class II cell-autonomously regulates self-renewal and differentiation of normal and malignant B cells

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