Novel Mechanism Found Behind Hyperactive Immune Responses

Excessive or prolonged immune responses can lead to chronic inflammation and other pathological conditions. So far, discoveries about the pathways behind this process have mostly involved effector molecules (cytokines) or cells downstream of the initial reaction. Recently, though, researchers at Yale School of Medicine have found a novel regulatory mechanism that occurs earlier at the interface between innate and adaptive immunity and controls the magnitude of the immune response, thus offering a new potential target for chronic and pathological inflammatory diseases.

Bridging Innate and Adaptive Immunity

When a pathogen enters the body, the innate immune system serves as the first line of defense. Specific parts of the pathogen (antigens) are recognized and presented by dendritic cells, which are the most potent type of antigen-presenting cell, to activate T cells that are part of the adaptive immune system. Dendritic cells thereby bridge communication between the innate and adaptive immune systems. Activated T cells can then proceed to proliferate and produce cytokines that will help fight off the pathogen.[1] But the dendritic cells from the beginning can still hypothetically keep activating more and more T cells, causing an increasingly bigger and bigger immune response.

This uncontrolled dendritic cell stimulation of T cells is exactly what has been implicated in the development of conditions such as autoimmunity and chronic inflammatory diseases.[2][3] So how do dendritic cells know when to stop? Previous research from Carla Rothlin, principal investigator of the lab at Yale, and others provided a clue when they showed that signaling through the TAM receptor tyrosine kinases play an important role in inhibiting activation of antigen-presenting cells as well as consequent cytokine production and inflammation.[4] While the ligands that bind to these receptors in vitro are Gas6 and Pros1 (Protein S), the source of the ligands in vivo was still unknown. One guess was that since dendritic cells tell T cells to start the immune response, maybe it was the T cells that could talk back to stop it.

Pros1 Signaling Figure

Searching for Protein S

To test the hypothesis that T cells produce the TAM receptor ligands, the Rothlin lab first started checking for T cell expression of Gas6 or Pros1 in vitro. Although T cells did not seem to produce any appreciable amount of Gas6, their levels of Pros1 expression appeared promising.[5] The researchers then moved to in vivo comparisons of normal mice versus conditional knockout mice with Pros1 deficient specifically only in CD4+ T cells. (Complete systemic Pros1 deficiency causes fatal bleeding disorders in utero, and Pros1 has been known to have other important non-immunological effects.) Upon activation, T cells from normal mice expressed Pros1 whereas Pros1-deficient mice did not. Mice deficient in protein S also had higher levels of activated dendritic cells and pro-inflammatory cytokines such as TNFα compared to control mice. Knocking out other components of the TAM signaling pathway had similar results, indicating that Pros1 proceeds through this pathway for its regulatory effect.

However, these differences in the magnitude of the immune response disappeared when dendritic cells and T cells were separated in a transwell system by a permeable but physical membrane. This experiment suggests that Pros1-TAM signaling requires physical cell-cell contact localized at the interface between dendritic cells and T cells as opposed to simply having a protein diffuse across to activate the pathway. Although Pros1 is a soluble protein, it requires binding to phosphatidylserine (PtdSer) for biological function. Because activated T cells transiently expose PtdSer on their cell membrane surface, Pros1 likely binds there and is thus restricted to a local area that requires cell-cell contact for signaling to occur. Key also is the timing, says Eugenio Antonio Carrera Silva, lead author of the paper. Throughout all of these experiments, T cells do not express Pros1 in their resting state but only after they have been activated and committed to mounting an immune response. The researchers were able to demonstrate as well that activated human T cells expressed Pros1 and that Pros1 neutralization with an antibody impaired the regulation of dendritic cells, thus successfully replicating their results from mice.

Protein S in Disease

In a mouse model of colitis (inflammatory bowel disease), the Rothlin lab demonstrated that Pros1 deficiency in immune cells caused exacerbated colitis. Colon tissue was visibly more inflamed, and lymph nodes in the area had higher levels of pro-inflammatory cytokines. In patients with inflammatory bowel disease, they found that plasma levels of Pros1 were often lower compared to healthy controls. Corroborating these findings are studies from as early as 1992 that have noted how protein S deficiency correlates with the disease.[6] Future work will have to determine to what extent the mechanism is due to T cell-specific Pros1 signaling.

So far, Protein S has mostly been known for its role in anticoagulation and phagocytosis of apoptotic cells[7] but not in immune cell signaling an inflammation. “TAM signaling is a totally new area in immunology,” says Carrera Silva. “Every single regulatory mechanism that we know we have to now also put side by side with TAM signaling.” More work is being done to further elucidate the interplay between this mechanism and other known regulatory mechanisms, such as anti-inflammatory IL-4 and IL-10 cytokines as well as regulatory T cells and macrophages. While cytokines diffuse around the bloodstream and can be the end product of many different pathways, signaling at the interface between dendritic cells and T cells provides an attractive local target for future drug therapy. Says Carrera Silva, “It’s opening a lot of doors for people to understand chronic inflammation, obesity, asthma, lupus, etc.”

References

  1. C. Reis e Sousa, 2011 ESCI Award for Excellence in Basic / Translational Research: innate regulation of adaptive immunity by dendritic cells, Eur. J. Clin. Invest. 41, p. 907–916, 2011.
  2. M. Wahren-Herlenius, T. Dörner, Immunopathogenic mechanisms of systemic autoimmune disease, The Lancet 382, pp. 819–831, 2013.
  3. J. H. Niess, Role of mucosal dendritic cells in inflammatory bowel disease, World J. Gastroenterol. 7, pp. 5138–5148, 2008.
  4. C. V. Rothlin, S. Ghosh, E. I. Zuniga, M. B.A. Oldstone, G. Lemke, TAM Receptors Are Pleiotropic Inhibitors of the Innate Immune Response, Cell 131, pp. 1124–1136, 2007.
  5. E. A. Carrera Silva, P. Y. Chan, L. Joannas, A. E. Errasti, N. Gagliani, L. Bosurgi, M. Jabbour, A. Perry, F. Smith-Chakmakova, D. Mucida, H. Cheroutre, T. Burstyn-Cohen, J. A. Leighton, G. Lemke, S. Ghosh, C. V. Rothlin, T Cell-Derived Protein S Engages TAM Receptor Signaling in Dendritic Cells to Control the Magnitude of the Immune Response, Immunity 39, pp. 160–170, 2013.
  6. E. Aadland, O.R. Odegaard, A. Røseth, K. Try, Free protein S deficiency in patients with chronic inflammatory bowel disease, Scand. J. Gastroenterol. 27, pp. 957–960, 1992.
  7. M. J. Heeb, Role of the PROS1 gene in thrombosis: lessons and controversies, Expert Rev. Hematol. 1, pp. 9–12, 2008.

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