Cytokine Regulation of MHC Molecules

• MHC molecule expression is regulated by cytokines via light source intensity control.
• Cytokines prompt specific transcription factor formation, upregulating genes for MHC class 1 and 2 protein development.
• Interferons (GABA, beta, and alpha) boost transcription factors binding to the MHC molecule promoter region, which upregulates genes and proteins involved in antigen processing and presentation.
• Inflammatory cytokines affect MHC expression and stem cell production.
• Dose-dependent increases in MHC class 1 and 2 are seen when cells are exposed to interferon-gamma and TNF-alpha.
• IL-6 did not increase MHC expression in the human neural stem progenitor cell line.
• MHC molecule regulatory role activates or recognizes T and B cells when bound.
• CD4 and CD8 positive T cells are critical for MHC regulation of the adaptive immune response.

Cytokine Regulation of MHC Molecules

• Cytokines like interferons (IFN-α, IFN-β, IFN-γ), tumor necrosis factor (TNF-α), and interleukins (IL-1, IL-6, IL-12) regulate MHC molecules and control their expression during immune responses, especially in inflammation.
• These cytokines are critical for enhancing MHC molecule expression improving antigen presentation, and activating the immune system.

Interferons (IFNs) Role in Regulating MHC Molecules

• Interferons, especially IFN-γ, are key regulators of MHC expression.
• IFN-γ (produced by T helper 1 cells, NK cells, and CD8+ T cells) is a potent inducer of both MHC class I and class II molecules.
• It enhances the expression of both MHC class I (important for CD8+ T cell responses) and MHC class II (important for CD4+ T cell responses).
• IFN-γ upregulates genes involved in antigen processing (e.g., proteasome components) and transport (e.g., TAP transporter), which results in more efficient presentation of cytosolic antigens (MHC Class I).
• IFN-γ induces the expression of CIITA (Class II transactivator), a transcription factor that activates MHC class II gene expression, enhancing antigen presentation (MHC Class II), especially by professional antigen-presenting cells (APCs) like dendritic cells, macrophages, and B cells.
• IFN-α and IFN-β (type I interferons) primarily increase MHC class I expression, particularly during viral infections, helping to boost the immune response against viral pathogens.

Tumor Necrosis Factor (TNF-α) Role in Regulating MHC Molecules

• TNF-α, produced by macrophages, dendritic cells, and T cells, plays an important role in regulating MHC expression.
• TNF-α enhances the expression of both MHC class I and II molecules, especially in response to infection or inflammation.
• It acts by stimulating NF-κB, a transcription factor that upregulates genes involved in immune responses, including those that control MHC expression.
• TNF-α also promotes the activation of immune cells like macrophages, further enhancing the expression of MHC molecules.
• It helps coordinate the immune response by inducing the expression of costimulatory molecules on APCs, which is crucial for T cell activation.
• MHC molecules are key regulators of immune system responsiveness.
• Immunomodulation is a key theme to understand several autoimmune and related diseases.

Experiments Demonstrating MHC Restriction

• Rosenthal and Shevach experiments (1970s) involved incubating guinea pig macrophages from strain two with antigen, then with T cells from the same or different strain animals.
• T cell proliferation magnitude was measured, confirming that CD4 positive T cells were activated and proliferated only with antigen presented by macrophages/APCs sharing class two MHC alleles.
• CD4 T helper cells are class two MHC restricted.
• Primed T cells did not recognize macrophage antigen presentation from animals of different strains, and so T cell proliferation did not occur.
• Zinkernagel and Doherty experiments in 1974 demonstrated MHC restriction of CD8 positive T cells.
• Mice were immunized with lymphocytic choriomeningitis virus, then CD8 positive T cells were isolated and incubated with virus-infected target cells of the same or different haplotype.
• Target cells were intracellularly labeled with CR 51, and CD8 positive T cell killing was measured.
• CD8 positive T cells only killed syngeneic virus-infected target cells expressing class one MHC molecules encoded by the K or D regions of the MHC.
• CD8 positive T cells are class one MHC restricted.
• T cells, CTLs, only kill target cells of the same haplotype and recognize antigen presented on MHC class one molecules.
• Two signals are needed: one from the supplement C and another from the antigen T cell to lyse cell, which identity restrictions.
• The discovery of MHC restriction happened by chance.

Self-MHC Restriction

• Self-MHC (Major Histocompatibility Complex) restriction refers to the phenomenon in the immune system where T cells specifically recognize and respond to antigens only when presented in the context of the individual's own MHC molecules.
• T cells undergo education in the thymus, learning to recognize self-MHC molecules.
• T cells not recognizing self-MHC with appropriate specificity or recognizing self-antigens too strongly are eliminated/rendered tolerant to prevent autoimmunity.
• T cells are activated and respond to antigens only when presented in the context of MHC molecules compatible with the individual's genetic makeup.
• The antigen recognition in association with self-MHC is a key aspect of the specificity and selectivity of the adaptive immune response.

Antigen Processing

• Antigen processing involves intracellular events where antigens are broken down into smaller peptide fragments.
• Fragments are presented on the cell surface bound to major histocompatibility complex (MHC) molecules.
• It is crucial for T cell activation, which plays a central role in the adaptive immune response.
• Antigen processing ensures the immune system recognizes a wide range of antigens and mounts specific immune responses against them.
• The recognition of antigens with MHC molecules is a key step in T cell activation and the initiation of adaptive immune responses.

MHC molecule expression is regulated by cytokines. Cytokines induce transcription factor formation, upregulating genes for MHC class 1 and 2 protein development. Interferons boost transcription factors binding for antigen processing and presentation. CD4 and CD8 positive T cells are critical for MHC regulation of the adaptive immune response.