Mycobacterium tuberculosis and Immune Evasion

Many of you have likely heard of tuberculosis (TB), a potentially lethal, infectious disease caused by intracellular bacterium called Mycobacterium tuberculosis. Although this bacterium usually attacks the lungs, it can also affect other parts of the body including the brain, the spine, or the kidneys. Tuberculosis germs are spread through the air, particularly when an infected person coughs, sneezes, or vocalizes. Symptoms of tuberculosis include weakness, a chronic cough, night sweats, fever, and weight loss. Tuberculosis is one of the world’s deadliest diseases. In 2012, there were 1.3 million tuberculosis related deaths worldwide (World Health Organization 2013). In fact, one-third of the world’s population is infected (Centers for Disease Control and Prevention 2013).

It is important to distinguish between two tuberculosis conditions: latent TB and active TB (also known as TB disease). Latent TB is defined by the presence of a TB infection, but the bacteria remain in the body remain inactive and do not cause symptoms. This is because the immune system acts to “wall off” the bacteria using a cellular structure called a granuloma which forms around the invaders. Active TB occurs when the immune system cannot prevent the TB bacteria from multiplying in the body. A person with active TB will be contagious and exhibit symptoms. People most susceptible to developing active TB disease are those who have been recently infected by TB bacteria or those with medical conditions that weaken the immune system such as HIV infection, tobacco use, or diabetes mellitus. Specifically, 90% of infected patients will have latent TB, while only 10% will progress to disease (World Health Organization 2013). TB is generally curable with antimicrobial drugs, but in many underdeveloped nations, access to such health care is unattainable. If untreated, 50% of active TB disease cases are fatal (World Health Organization 2013). Additionally, resistance to the medicines is increasing. This is evidenced by the emergence of multi-drug resistant TB, which is the result of bacteria that do not respond to standard anti-TB drugs (Centers for Disease Control and Prevention 2013).

Clearly, TB is a relevant concern in today’s world. An October 2013 study by Heuer et al. (http://www.biomedcentral.com/1471-2172/14/48) examined the effects of two Mycobacterium tuberculosis antigens on human dendritic cell maturation and how this affects immune response. This study was investigating the viability of these antigens as vaccine candidates, while also examining how these antigens may be involved in immune reaction or immune evasion. Antigens are entities (in this case, an element of the Mycobacterium tuberculosis) that can bind to the antigen receptor of a T or B cell (leukocytes that mediate adaptive immunity). Dendritic cells are phagocytic leukocytes that process antigen material and function as antigen presenting cells. Specifically, infection of these dendritic cells by Mycobacterium tuberculosis leads to the downregulation of the expression of MHC class I and II and CD1 (cell surface proteins which present antigens to T cells). Therefore, if there are less of these antigen presentation molecules, antigens will not be effectively presented to T cells and NKT cells so effective immune responses won’t be promoted. This suboptimal immune response is considered to be a cause of susceptibility to Mycobacterium tuberculosis.

Most people control tuberculosis through NK cell and Th1 immune responses, characterized specifically by the release of IFN-γ (a cytokine that acts as a macrophage activator) and TNF (a cytokine that causes cell death) leading to the cytotoxic activity of CD8⁺  T cells and macrophages (Schluger & Rom 1998). As mentioned above though, pathogens like Mycobacterium tuberculosis are able to employ mechanisms of immune invasion, which lead to the persistence of the microbes. The mechanism that is mentioned in this paper refers to the ability of the Mycobacterium tuberculosis antigens to induce only partial DC maturation, which in turn leads to a Th2 shift with regards to T cell polarization (polarization refers to differentiation into the Th1 versus Th2 subset). This is a form of immune evasion because effective immune protection from intracellular bacteria like Mycobacterium tuberculosis relies on IFN-γ dependent CD4⁺ Th1 and cytotoxic CD8⁺ T cell responses. Therefore, this T cell polarization shift at the level of DCs offers a mechanism of immune evasion.

The Th1 response is most suitable for intracellular pathogens, while the Th2 response is more appropriate for extracellular pathogens (Mossman & Coffman 1989). The most important Th1 interactions are with macrophages, while significant Th2 interactions are with B cells. Th1 cells produce IFN-γ, IL-2, and TNF-β (cytokines that assist in adaptive responses against intracellular threats) (Romagnani 2000). They evoke cell mediated immunity and phagocyte dependent inflammation. Naïve CD4⁺ T cells are polarized to the Th1 effector subset by IL-12 and IFN-γ (Schluger & Rom 1998). Th2 cells produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13 (cytokines that assist in adaptive responses against extracellular threats) (Romagnani 2000). They evoke strong antibody responses, but actually inhibit several functions of phagocytic cells. Naïve CD4⁺ T cells are polarized to the Th2 effector subset by IL-4 and IL-6 (Schluger & Rom 1998). A high Th1 response is therefore expected to lead to enhancement of cytotoxic mechanisms (which are appropriate for dealing with intracellular infections), while a preferential Th2 response promotes increased antibody levels (more suitable for extracellular infections) (Berger 2000). Consequently, since Mycobacterium tuberculosis is an intracellular pathogen, a preferential Th1 response is more desirable. The ability of the Mycobacterium tuberculosis antigens to instead facilitate a Th2 response is consequently a mechanism of immune invasion.

In this paper, the authors developed a human CD4⁺ T cell proliferation assay to test the polarization of T cells, and ultimately to determine if the antigens shifted immune responses toward Th2, which, as explained above, would be a sign of immune evasion. The two antigens were found to induce only a partial DC maturation (as indicated by low stimulatory capacities, only mild upregulation of typical maturation markers, and only moderate DC cytokine production; see Figures 1 & 2 of Heuer et al. 2013 paper) that may lead to a tolerogenic or immune deviatory CD4⁺ Th2 cell response. This is because differential DC maturation conditions have been found to dictate Th1/Th2 polarization responses (Lutz 2013). Th1 responses associate with fully mature DCs, while Th2 responses are linked to partially matured DCs (Lutz 2013). It is also important to note that T cells that were stimulated by the two antigen-matured DCs maintained high IL-4 production (see Figure 4 of Heuer et al. 2013 paper), which was a sign of immune evasion since IL-4 is produced by the Th2 response. Therefore, just as immature DCs express a bias towards Th2 polarization, DCs matured with the Mycobacterium tuberculosis antigens are also biased towards Th2 polarization. Ultimately, since these antigens do not induce strong CD8 and Th1 memory responses while avoiding immune tolerance mechanisms, they are not good candidates for successful vaccines.

To summarize, the authors of this study determined that two Mycobacterium tuberculosis antigens promote a Th2 shift, which serves as a form of immune evasion and makes the body more susceptible to the development of tuberculosis. This is because the Th2 cell response is suited for extracellular pathogens, but Mycobacterium tuberculosis is an intracellular pathogen. The Th2 response is facilitated by the induction of only partial DC maturation by the antigens and by the fact that even Mycobacterium tuberculosis antigen matured DCs maintained high IL-4 production. This partial DC maturation and high IL-4 production is indicative of a Th2 response, providing support for the notion that the antigens promote a Th2 cell response, rather than the desired Th1 cell response for combating an intracellular pathogen. This deviation of the immune response toward a Th2 profile is thus a mechanism of immune evasion, and allows for the persistence of the Mycobacterium tuberculosis microbes.

This paper is highly relevant because of the significant role that tuberculosis continues to play in the world, namely as a major cause of death among infectious diseases. It’s an interesting paper in that it examined specific Mycobacterium tuberculosis antigens in the context of DC maturation and immune deviation. However, this study was performed in vitro. Therefore, further studies should seek to validate the claims of this paper in vivo. Further studies might also expand this experiment to examine other Mycobacterium tuberculosis antigens, in an attempt to identify optimal vaccine candidates that can induce strong CD8 and Th1 responses, rather than experiencing immune deviation towards a Th2 response (which is indicative of infections leading to microbial persistence). Ultimately, an antigen that can induce DC cell maturation and promote enhanced cellular immunity is essential for the development of an effective TB vaccine. Finding an effective and safe tuberculosis vaccine would be a major step towards improving global health. 

        

References:

Primary Article:

Heuer, M., Behlich, A.S., Lee, J.S., Ribechini, E., Jo, E.K., & Lutz, M.B. (2013). The 30-kDa and 38-kDa antigens from Mycobacterium tuberculosis induce partial maturation of human dendritic cells shifting CD4⁺ T cell responses towards IL-4 production. BMC Immunology, 14(48).

http://www.biomedcentral.com/1471-2172/14/48

Additional Sources:

Berger, A. (2000). Th1 and Th2 responses: what are they? BMJ, 321(7258): 424.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC27457/

Centers for Disease Control and Prevention. (2013). Tuberculosis (TB). USA.gov. Retrieved from http://www.cdc.gov/tb/.   

Lutz, M.B. (2013). How quantitative differences in dendritic cell maturation can direct Th1/Th2-cell polarization. Oncoimmunology, 2(2).

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601159/

Mossman, T.R. & Coffman, R.L. (1989). Th1 and Th2 cells: Different patterns of lymphokine       secretion lead to different functional properties. Annual Review of Immunology, 7:145-173.
      http://www.annualreviews.org/doi/pdf/10.1146/annurev.iy.07.040189.001045

Romagnani, S. (2000). T cell subsets (Th1versus Th2). Annals of Allergy, Asthma, & Immunology, 85(1): 9-18.
     http://www.ncbi.nlm.nih.gov/pubmed/10923599

Schluger, N.W. & Rom, W.N. (1998). The host immune response to tuberculosis. American Journal of Respiratory Care and Medicine, 157(3): 679-691.
    http://www.atsjournals.org/doi/full/10.1164/ajrccm.157.3.9708002#.UnkX8b8o7IU

World Health Organization. (2013). Tuberculosis. WHO.int. Retrieved from http://www.who.int/mediacentre/factsheets/fs104/en/.

Images:

Eldridge, L. (2011). Tuberculosis increases risk of lung cancer. About.com. Retrieved from http://lungcancer.about.com/b/2011/01/01/tuberculosis-increases-risk-of-lung-cancer.htm.

Lutz, M. (2012). Therapeutic potential of semi-mature dendritic cells for tolerance induction. Frontiers in Immunology, 3(123).
      http://www.frontiersin.org/Journal/10.3389/fimmu.2012.00123/full

Peterson, D. (2012). Am I Th1 or Th2 or Th17? Living Wellness. Retrieved from http://livingwellnessblog.wordpress.com/2012/10/12/am-i-th1-or-th2-or-th17/.

Todar, K. (2012). Mycobacterium tuberculosis and tuberculosis. Textbook of Bacteriology. Retrieved from http://textbookofbacteriology.net/tuberculosis.html.

World Health Organization. (2012). World: Estimated tuberculosis (TB) incidence rates, 2011 (as of 5 Nov 2012). WHO.int. Retrieved from http://reliefweb.int/map/world/world-estimated-tuberculosis-tb-incidence-rates2011-5-nov-2012.