The Missing Link in T-cell activation using a Vaccine, "The Danger Signal" may be due to an enzyme called IDO -2013
The Missing Link in T-cell activation using aVaccine, "The Danger Signal" may be due toan enzyme called IDOAs I research why some patients respond to therapies i.e. vaccination and other immunotherapyand others don’t, I ask WHY? In my quest to get the answer or answers, I came across a papercalled “Marked Differences in Human Melanoma Antigen-Specific T CellResponsiveness after Vaccination Using a Functional Microarray”.Daniel S. Chen1,2#, Yoav Soen3#, Tor B. Stuge4, Peter P. Lee4, Jeffrey S. Weber5, Patrick O. Brown2,3, Mark M.Davis2,6*1 Department of Internal Medicine/Division of Oncology, Stanford University, Stanford, California, UnitedStates of America, 2 Howard Hughes Medical Institute, Stanford University, Stanford, California, UnitedStates of America, 3 Department of Biochemistry, Stanford University, Stanford, California, United Statesof America, 4 Department of Medicine, Stanford University, Stanford, California, United States ofAmerica, 5 Norris Cancer Center, University of Southern California, Los Angeles, California, United Statesof America, 6 Department of Microbiology and Immunology, Stanford University, Stanford, California,United States of AmericaThis is what I was looking for. It may hold the answer or could possibly point me in the rightdirection.In the paper I came across a diagram that peaked my interest. It was a comparison betweenresponders and non-responders.
We concluded from these studies that IL-1 and perhaps IL-6 play a critical role in thedifferentiation and expansion of Th17 cells. Yoshihiro Miyahara et al +IL-6 controls Th17 immunity by inhibiting the conversion of naive CD4 T cells into +Foxp3 regulatory T cells.Using in vitro and in vivo approaches, we determined that under neutral conditions,simultaneous activation of Tregs and naive CD4+ conventional T cells in the presence ofAPCs resulted in conversion of Tregs into IL-17–producing cells, and endogenous IL-1βwas mandatory in this process according to Vassiliki A. Boussiotis et al. “IL-1β–Mediated Signals Preferentially Drive Conversion of Regulatory T Cells but NotConventional T Cells into IL-17–Producing Cells”IL-6 protects CD4 T cells from cell death but also inhibits the suppressive effect of Tregs.“Thus, the addition of IL-6 to the tumor microenvironment skews the balance towardTh17 cells in a murine model of pancreatic cancer. The delayed tumor growth andimproved survival suggests that induction of Th17 in the tumor microenvironmentproduces an antitumor effect.” David C. Linehan et alThey were looking at the cytokines secreted after the vaccine was given. When I saw what thecytokines were, I knew I was on the right track. These cytokines help in the differentiation of theCD4+ T-cells. What a find!!
Naïve CD4 T cells in the presence of TGF-b and IL-2 and others differentiate intoTregs.TGF-b accelerates the CTLA-4 expression by stimulated CD4+ CD25- T-cellsTGF-b requires CTLA-4 early after T-cell activation to induce FoxP expressiongenerating CD4+ CD25+ Treg Regulatory cells.The Th-17 cells produce IL-17. .IL-17 induces the production of many other cytokines(such as IL-6, G-CSF, GM-CSF, IL-1β, TGF-β, TNF-α)
So what was the non-responder missing, IL-6. With the missing IL-6, they weren’t ableto produce Th-17 that secreted IL-17.While TGF-β is a critical differentiation factor for Treg cells, IL6 completely inhibits thegeneration of Treg cells induced by TGF-β. Instead, IL6 and TGF-β together induce thedifferentiation of pathogenic Th17 cells. With IL-6 missing in the microenvironment,Treg Cells flourish.If the CD4 + T cells differentiate into TH2 cells that produce IL-4, the other cellsinhibited to produce IL-6. IL-4 was found to inhibit TNF-α and IL-1β by activatedmonocytes almost 100 %. The Secretion of IL-6 was decreased by approximatly 80 % inthe presences of IL-4 Cytokine. TE Velde et al 1990
They were missing “The Danger Signal”.Friendly inflammation “The Danger Signal”Most of the time you have no notion of the microbial life-and-death struggle being wagedwithin your body. At other times, though, you are acutely aware of the exact location ofthe battleground, thanks to the unmistakable signs of inflammation — heat, pain, redness,and swelling. Inflammation, the buildup of fluid and cells at the point of infection/cancer,is put into motion by cytokines — proteins that are released into the blood by the innateimmune system when it encounters germs. Cytokines function like police dispatchers.They signal theres a problem, which activates the immune systems highway patrol force:the circulating lymphocytes of the adaptive immune system. These lymphocytes cruisethe highways of the blood vessels and lymphatic system. In response to the chemicalsignal from the cytokines, increased blood flow rushes these circulating cells to thetrouble spot.“The CD8+ T-cell-mediated Immune Response to Eradicate the Tumors” “Three major events must occur to induce CD8+ T cell–mediated, tumor-protectiveimmunity against syngeneic melanoma. First, the T-cell receptor must be triggered by a(or multiple) self antigen–derived peptide MHC class I complex . Therefore, this eventdepends entirely on appropriate antigen presentation, which is most efficiently providedby mature dendritic cells. Peripherally tolerant or “ignorant” self-reactive T-cell clones,once properly activated, may serve as tumor-specific effector T cells .Second,simultaneously with T-cell receptor triggering, a distinct second costimulatory signalmust be delivered, mediated by IL-2, B7-1, or B7-2, which engage IL-2 receptors andCD28 on the surface of the T cell, respectively. A source of these cofactors for effectiveCD8+ T-cell stimulation can be provided by CD4+ T cells that release critical amounts ofIL-2, or by mature dendritic cells that display an increased level of B7-1/B7-2costimulatory molecules on their cell surfaces. Third, inflammatory cytokines,including IL-1, IL-6, IL-12, IL-17 and IFN-γ provide a third signal that acts directlyon T cells, referred to as the “danger signal”. This signal was found to optimallyactivate TH1 differentiation and lead to clonal expansion of T cells.
The responder was able to produce inflammatory cytokines, including IL-1, IL-6, IL-12,IL-17 and IFN-γ provides a third signal that acts directly on T cells, referred to as the“danger signal”. This signal was found to optimally activate TH1 differentiation and leadto clonal expansion of T cells and invoke a robust immune response to the MelanomaCancer.
Conclusion: Based on my observation, the cytokine that ties this “Danger Signal” to theimmune system is IL-6. • IL-6 protects CD4 T cells from cell death but also inhibits the suppressive effect of Tregs. • IL-6 controls Th17 immunity by inhibiting the conversion of naive + + CD4 T cells into Foxp3 regulatory T cells.
So what is causing the lack of IL-6 in the non-responders? The IDO enzyme. Thisenzyme catalyzes the degradation of the essential amino acid L-tryptophan to N-formylkynurenine.IDO enzyme degrades tryptophan and through the GCN2 kinase pathway inhibits thetranscription of IL-6. Without the transcription of IL-6, the IL-6 cytokine cannot beproduced leading to the T-cell differentialtion toward the T Regulatory cell instead of theTH17 phenotype.My guess is the tumor induced enzyme called IDO may the Missing Link to intiating animmune response.IDO produced by Tumor cells significantly inhibited interleukin (IL-2) expression and proliferative response in T-cells and increased apoptosis (death) of T-
cells. Tryptophan depletion is known to halt cell cycle progression by triggering theantiproliferative GCN2 pathway in lymphocytes.Also, IDO is upregulated in antigen-presenting dendritic cells (DC) by autocrine IFN-γreleased as a result of Treg cell–induced CTLA-4/B7-dependent cell-cell signaling.It is well established that IDO expression by APCs or tumors can inhibit immuneresponses.Tryptophan depletion by IDO-expressing tumors is a common mechanism ofimmune evasion inducing regulatory T cells and inhibiting effector T cells.So adding IDO inhibitor to a combinatorial therapy like Yervoy for melanoma cancershould see a syenergist response