CIITA – The Master Regulator Gene

By Daniella Gimbosh

The Class II Major Histocompatibility Complex (MHC-II) Transactivator gene, or CIITA gene, has earned the name of the “master regulator gene” – and rightfully so. CIITA, and its gene product, the CIITA protein, is known as the ‘master regulator’ of MHC-II gene transcription, which, in turn, codes for the MHC-II molecules present on the surface of professional antigen presenting cells (APCs) such as dendritic cells, macrophages and B cells. These APCs are vital for survival as they present proteins, known as antigens, from the dangerous pathogens that have managed to wiggle through the strong defenses of the body. Thus, the role of the MHC-II molecules, and the CIITA gene, is undeniably crucial for the human body to be able to effectively fend off foreign invaders (Harton & Ting, 2000). 

CIITA does not seem to directly bind DNA, but instead interacts with and regulates DNA-bound transcription factors at the MHC-II gene promoter. There is also evidence that CIITA contributes to the transcription of MHC-I and over 60 other immunologically relevant genes (Devaiah & Singer, 2013). The MHC-II molecules have a vital role in the adaptive immune response as they present extracellular antigens on APCs to CD4 positive T cells, otherwise known as T helper cells, during antigen presentation. This is critical for antigen recognition, as the specific peptide presented controls how the ferocious T helper cells will respond to the infection and which chemicals, known as antigen-specific cytokines, will be released to fight the pathogen. 

Furthermore, when maturing in the germinal centre of the lymph nodes, B cells can survive and differentiate by presenting antigens on MHC-II to T helper effector cells. These T helper cells are activated, leading, in turn, to the activation of cytotoxic and natural killer cells, whose role is to destroy damaged or infected cells. Furthermore, MHC-II molecules have another important role: ensuring that the T cells of the body do not react to ‘self’ antigens, antigens that are part of the host, in a process known as tolerance. This is a process designed to stop inappropriate immune responses to non-pathogenic antigens, helping to prevent auto-immune diseases. 

Antigen presentation to T helper cells allows them to signal back to the APC to stimulate more radical action against the pathogen, for example, by sending effector molecules such as IL-4 to B cells to stimulate their differentiation into plasma or memory B cells. MHC-II also ensures that peptides are bound tightly, which is needed to prevent detachment and degradation of the antigen. This seemingly inconsequential job is critical, as detachment of the antigen would inhibit antigen recognition, T cell recruitment and activation, and a proper immune response, leaving the host vulnerable to disease (Jurewicz & Stern, 2019). The triggered immune response may include localized inflammation due to recruitment of white blood cells, or a full-force antibody response due to B cell activation.

CIITA is constitutively expressed only on professional APCs, however, non-professional APCs can also regulate CIITA and MHC II expression. For example, cytokines such as interferon-gamma may induce CIITA expression and are responsible for converting MHC-II negative white blood cells, such as monocytes, into functional MHC-II positive APCs, known as inducible expression. Moreover, CIITA acts as a viral restriction factor by repressing viral replication to control infections, such as with the Human T-cell lymphotropic virus (Butowt, Pyrc & von Bartheld, 2020).

Therefore, it comes as no surprise that various mutations in the CIITA gene have immense impacts on the immune system, as they may lead to CIITA protein deficiency, resulting in decreased or aberrant MHC gene expression. This deficit means that T cells may not mature properly, there may be a significant decrease in T cell abundance and even a lack of antibody production by B cells. Furthermore, with a lack of CIITA, selection of T helper cells, maturation of B cells and tolerance would all be impacted, and a decrease in natural killer and cytotoxic T cell activity would be seen; all crucial players in adaptive immunity. These factors, among others, can lead to an incomplete and disrupted immune response that could result in a myriad of diseases including autoimmune diseases such as Type II bare lymphocyte syndrome (or BLS), rheumatoid arthritis, cancers, viral entry and more (Swanberg et al., 2005). 

Perhaps the most drastic of these diseases is BLS. This immunodeficiency disorder caused by CIITA mutation results in a severe reduction or absence of MHC-II on APCs. This means that the immune system is effectively ignoring invading pathogens as there is a lack of antigen recognition by T cells and therefore a severe deficit in both cellular and humoral immune response to antigens. Patients therefore lack T and B cell function and have a decreased proportion of T helper cells overall due to reduced T helper cell selection in the thymus. This results in recurrent infections such as in the gastrointestinal and respiratory tracts, which often leads to the malabsorption of nutrients, organ failure and death within early childhood (Reith & Mach, 2001). 

Finally, it has been found that various CIITA mutations are often present in tumour cells, including primary mediastinal large B cell lymphoma (Mottok et al., 2015). This suggests that CIITA mutations and decreased MHC-II expression may result in tumour cells evading the immune system, and possibly implicates this gene in cancer. The reduced ability of tumour cells to induce an immune response in MHC-II negative tumours results in a “cold” tumour microenvironment where there is a severe lack of immune cells seeking to destroy the cancer, as opposed to the inflamed or “hot” microenvironment of MHC-II positive tumours (Accolla et al., 2014). Introducing CIITA into tumours could therefore be a potential target in cancer therapy (Accolla et al., 2019). 

Nonetheless, which genes CIITA activates and which immune pathways this could affect, is still very much an open question for future research. 

References

Harton, J.A. & Ting, J.P.-Y. . (2000) Class II Transactivator: Mastering the Art of Major Histocompatibility Complex Expression. Molecular and Cellular Biology. [Online] 20 (17), 6185–6194. Available from: doi:10.1128/mcb.20.17.6185-6194.2000 [Accessed: 13 March 2021].

Devaiah, B.N. & Singer, D.S. (2013) CIITA and Its Dual Roles in MHC Gene Transcription. Frontiers in Immunology. [Online] 4, 476. Available from: doi:10.3389/fimmu.2013.00476 [Accessed: 13 March 2021].

Jurewicz, M.M. & Stern, L.J. (2019) Class II MHC Antigen Processing in Immune Tolerance and Inflammation. Immunogenetics. [Online] 71 (3), 171–187. Available from: doi:10.1007/s00251-018-1095-x [Accessed: 16 March 2021].

Butowt, R., Pyrc, K. & von Bartheld, C.S. (2020) Battle at the entrance gate: CIITA as a weapon to prevent the internalization of SARS-CoV-2 and Ebola viruses. Signal Transduction and Targeted Therapy. [Online] 5 (1), 1–2. Available from: doi:10.1038/s41392-020-00405-2 [Accessed: 16 March 2021].

Swanberg, M., Lidman, O., Padyukov, L., Eriksson, P., et al. (2005) MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nature Genetics. [Online] 37 (5), 486–494. Available from: doi:10.1038/ng1544 [Accessed: 14 March 2021].

Reith, W. & Mach, B. (2001) The bare lymphocyte syndrome and the regulation of MHC expression. Annual Review of Immunology. [Online] 19 (1), 331–373. Available from: doi:10.1146/annurev.immunol.19.1.331 [Accessed: 12 March 2021].

Mottok, A., Woolcock, B., Chan, F.C., Tong, K.M., et al. (2015) Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression. Cell Reports. [Online] 13 (7), 1418–1431. Available from: doi:10.1016/j.celrep.2015.10.008 [Accessed: 15 March 2021].

Accolla, R.S., Lombardo, L., Abdallah, R., Raval, G., et al. (2014) Boosting the MHC Class II-Restricted Tumor Antigen Presentation to CD4+ T Helper Cells: A Critical Issue for Triggering Protective Immunity and Re-Orienting the Tumor Microenvironment Toward an Anti-Tumor State. Frontiers in Oncology. [Online] 4 (32), 32. Available from: doi:10.3389/fonc.2014.00032 [Accessed: 14 March 2021].

Accolla, R.S., Ramia, E., Tedeschi, A. & Forlani, G. (2019) CIITA-Driven MHC Class II Expressing Tumor Cells as Antigen Presenting Cell Performers: Toward the Construction of an Optimal Anti-tumor Vaccine. Frontiers in Immunology. [Online] 10 (), 1806. Available from: doi:10.3389/fimmu.2019.01806 [Accessed: 16 March 2021].

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