T cells and the Immune Response

T helper cell AICD modulates the Immune response

The immune system organizes defence against pathogens through finely tuned innate and adaptive arms that have intricate and regimented positive and negative feedback loops. T cells come under the adaptive immune response arm and antigen presentation to these cells causes them to proliferate, produce cytokines and counter pathogen(s). Multiple factors including the presence of pathogen associated products, cytokine combinations and or their altered levels influence preferential development of antigen specific cytotoxic or helper T cells but the exact mechanisms are still being studied. It is of significance that biased T cell activation is crucial in countering infectious agents, both intra and extra cellular, that is encountered during a life time. Interestingly differentially activated T cell subsets have completely contrasting effects on the immune system and are mutually counterproductive in disease conditions when the opposite subset is required. The presence of unwanted T cell subsets have been noted in chronic diseases such as Arthritis, Asthma, AIDS, Tuberculosis and helminth infections and their persistence have been hallmarks of poor prognosis. Recent studies have shown that pathogen associated products and or loss in immune regulation seem to drive the unwanted T cell subset. Subsequently for therapeutic interventions it is critically important to remove the unwanted T cell subset and re establish the preferred T cell. To that end we will use the balance of pro and anti apoptotic proteins that are differentially regulated by cytokines and target them to attempt manipulation of the immune responses.

Novel T Helper subset promotes Immune Responses through GM-CSF

T helper cells are critical in maintaining immune responses but have an undefined relationship with GM-CSF, one of the most potent immune stimulatory cytokines. By depleting major cytokines during CD4+ T cells differentiation in vitro, we obtained a novel subset of T helper cells (ThGM), that produced significantly higher amounts of GM-CSF than other T helper subsets. Interestingly, ThGM cells through GM-CSF, helped cytokine production by Th1, Th2, Tc1, Tc2 and nave T cells. DC differentiation with GM-CSF alone up regulated DC-SIGN significantly while anti-GM-CSF antibody supplementation abolished the cytokine augmentation properties of ThGM cells. Furthermore, ThGM cells are prone to AICD and express elevated levels of pro-apoptotic proteins, such Bid and Bim. Inhibitors of FasL, TRAIL, caspase 8 or granzymes could not inhibit AICD in ThGM cells. Thus, ThGM cells are a novel T helper population that produces GM-CSF, exhibits high susceptibility to apoptosis, and could play an important role in regulating immune responses.

Cytotoxic T cell AICD could bias Immune Response through IL-10

Cytotoxic T cells can be differentiated into type 1 (Tc1) and type 2 (Tc2) as their T helper counterparts. Interestingly, TCR-ICD mechanisms reveal that CD95L mediates cell death in Tc1 cells while Tc2 cells require TRAIL, Bim and caspases. Inhibiting TRAIL binding in wild type mice and Tc2 cells from TRAIL KO mice displayed altered Tc2 death while pan caspase inhibitors blocked AICD in both Tc1 and Tc2 subsets. Rescued Tc2 cells from Wild type or Tc2 TRAIL KO mice secreted significantly higher amounts of IL-10 along with IL-4 and IL-5 while Tc1 cells produced IFN- and TNF-. Interestingly chronic activation of T cells resulted in IL-10 secreting CD8 cells that dominate through FasL mediated killing of CD4 cells while CD8 T cell differentiated in the presence of IL-10 upregulated Serine Protease Inhibitors- 6 and 2A. We conclude that pathogens could alter the immune response by affecting TCR-ICD of cytotoxic T cells through IL-10 and by affecting TCR-ICD.

T cells and the Immune Response

Publication List:

1. Sengupta S, Bhattacharya G, Mohanty S, Shaw SK, Jogdand GM, Jha R, Barik PK, Parida JR, Devadas S. IL-21, Inflammatory Cytokines and Hyperpolarized CD8+ T Cells Are Central Players in Lupus Immune Pathology. Antioxidants (Basel). 2023 Jan 12;12(1):181. doi: 10.3390/antiox12010181. PMID: 36671045; PMCID: PMC9855022.
2. Sengupta S, Shaw SK, Chatterjee S, Bhattacharya G, Barik PK, Chattopadhyay S, Devadas S. Perturbations in spike-specific peripheral T follicular helper cells in SARS-CoV2 breakthrough convalescent individuals immunized by BBV152 vaccine. J Med Virol. 2023 Sep;95(9):e29053. doi: 10.1002/jmv.29053. PMID: 37650214.
3. Sengupta S, Bhattacharya G, Chatterjee S, Datey A, Shaw SK, Suranjika S, Nath P, Barik PK, Prasad P, Chattopadhyay S, Swain RK, Parida A, Devadas S. Underlying Co-Morbidity Reveals Unique Immune Signatures in Type II Diabetes Patients Infected With SARS-CoV2. Front Immunol. 2022 Apr 27;13:848335. doi: 10.3389/fimmu.2022.848335. PMID: 35572555; PMCID: PMC9094480.
4. Chatterjee S, Datey A, Sengupta S, Ghosh A, Jha A, Walia S, Singh S, Suranjika S, Bhattacharya G, Laha E, Keshry SS, Ray A, Pani SS, Suryawanshi AR, Dash R, Senapati S, Beuria TK, Syed GH, Prasad P, Raghav SK, Devadas S, Swain RK, Chattopadhyay S, Parida A. Clinical, Virological, Immunological, and Genomic Characterization of Asymptomatic and Symptomatic Cases With SARS-CoV-2 Infection in India. Front Cell Infect Microbiol. 2021 Dec 21;11:725035. doi: 10.3389/fcimb.2021.725035. PMID: 34993157; PMCID: PMC8724424.
5. Mohanty S, Barik P, Debata N, Nagarajan P, Devadas S. iCa²⁺ Flux, ROS and IL-10 Determines Cytotoxic, and Suppressor T Cell Functions in Chronic Human Viral Infections. Front Immunol. 2020 Mar 6;11:83. doi: 10.3389/fimmu.2020.00083. PMID: 32210950; PMCID: PMC7068714.
6. Inducible Costimulator Expressing T Cells Promote Parasitic Growth During Blood Stage Plasmodium berghei ANKA Infection. Jogdand GM, Sengupta S, Bhattacharya G, Singh SK, Barik PK1, Devadas S. Front Immunol. 2018 May 28;9:1041. doi: 10.3389/fimmu.2018.01041.
7. Autoreactive T Cells in Immunopathogenesis of TB-Associated Uveitis. Tagirasa R, Parmar S, Barik MR, Devadas S, Basu S. Invest Ophthalmol Vis Sci. 2017 Nov 1;58(13):5682-5691. doi: 10.1167/iovs.17-22462.
8. Jogdand GM, Mohanty S, Devadas S. Regulators of Tfh Cell Differentiation. Front Immunol. 2016 Nov 23;7:520. doi: 10.3389/fimmu.2016.00520. PMID: 27933060; PMCID: PMC5120123.
9. Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells. Abimannan T, Peroumal D, Parida JR, Barik PK, Padhan P, Devadas S. Free Radic Biol Med. 2016 Aug 24;99:352-363.
10. Inherent low Erk and p38 activity reduce Fas Ligand expression and degranulation in T helper 17 cells leading to activation induced cell death resistance. Peroumal D, Abimannan T, Tagirasa R, Parida JR, Singh SK, Padhan P, Devadas S. Oncotarget. 2016 Jul 28.
11. A novel subset of helper T cells promotes immune responses by secreting GM-CSF. Zhang J, Roberts AI, Liu C, Ren G, Xu G, Zhang L, Devadas S, Shi Y. Cell Death Differ. 2013 Dec;20(12):1731-41.
12. Swaims A Y, Lin H, Simon P, Granier C, Zhang Y, Roberts A I, Devadas S, Shi Y, Rabson A B. Activation of HTLV-1 expression in chronically-infected CD4+ T cells: mechanisms and implications for pathogenesis. Retrovirology. 2011; 8(Suppl 1): A6. Published online 2011 June 6.
13. Swaims A Y, Khani F, Zhang Y, Roberts A I, Devadas S, Shi Y, Rabson A B. Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells. Blood. 2010 October 21; 116(16): 2994–3003.
14. Swaims A Y, Granier C, Khani F, Zhang Y, Roberts A I, Devadas S, Shi Y, Rabson A B. Modeling HTLV-lymphomagenesis: immune activation induces immortalization and leukemogenicity of HTLV-1 LTR-Tax transgenic CD4+T-cells. Retrovirology. 2009; 6(Suppl 2): P73. Published online 2009 September 24.
15. Devadas S, Das J, Liu C, Zhang L, Roberts A, Pan Z, Moore P, Das G, Shi Y. Granzyme B is critical for T cell receptor-induced cell death of type 2 helper T cells. Immunity. 2006 Aug; 25(2):237-47.
16. Shi Y, Liu CH, Roberts AI, Das J, Xu G, Ren G, Zhang Y, Zhang L, Yuan ZR, Tan HS, Das G, Devadas S. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don’t know. Cell Res. 2006 Feb; (2):126-33.
17. Devadas S*, Jackson SH, Jaeyul Kwon, Ligia Pinto and Mark S. Williams (*Co-first author). T cells express an NAD(P)H oxidase that contributes to TcR stimulated generation of reactive oxygen species. Nature Immunology Aug 2004 5(8):818-27.
18. Devadas S, Hinshaw JA, Zaritskaya L, Williams MS. Fas-stimulated generation of reactive oxygen species or exogenous oxidative stress sensitize cells to Fas-mediated apoptosis. Free Radic Biol Med. 2003 Sep 15; 35(6):648-61.
19. Kwon J, Devadas S, Williams MS. T cell receptor-stimulated generation of hydrogen peroxide inhibits MEK-ERK activation and lck serine phosphorylation. Free Radic Biol Med. 2003 Aug 15; 35(4): 406-17.
20. Zhang XR, Zhang LY, Devadas S, Li L, Keegan AD, Shi YF. Reciprocal expression of TRAIL and CD95L in Th1 and Th2 cells: role of apoptosis in T helper subset differentiation. Cell Death Differ. 2003 Feb; 10(2):203-10.
21. Devadas S, Greeneltch KM, Yin D, Allan Mufson R, Zhou JN. Stressed to death: implication of lymphocyte apoptosis for Psychoneuroimmunology. Shi Y. Brain Behav Immun. 2003 Feb;17 Suppl 1:S18-26.
22. Roberts AI, Devadas S, Zhang X, Zhang L, Keegan A, Greeneltch K, Solomon J, Wei L, Das J, Sun E, Liu C, Yuan Z, Zhou JN, Shi Y. The role of activation-induced cell death in the differentiation of T-helper-cell subsets. Immunol Res. 2003; 28(3):285-93.
23. Devadas S, Luba Zaritskaya, Sue Goo Rhee, Larry Oberley and Mark S. Williams. Discrete Generation of Superoxide and Hydrogen Peroxide by T-Cell Receptor Stimulation Selective Regulation of Mitogen-Activated Protein Kinase Activation and Fas Ligand Expression. J Exp Med 2002 Jan 7; 195 (1):59-70.

Book Publication:

1. Shi, YF, Devadas, S, Zhang, XR, Zhang, LY, Keegan, A, Greeneltch, K, Solomon, JC, Yuan, ZR, Sun, EW, Liu, C, Das, J, Thayyil-Satish, M, Wei, LX, Zhou, JN and Roberts, A. Activation-Induced Cell Death and T Helper Subset Differentiation. In Shi, Y. F., Cidlowski, J., Scott, D. W. and Shi, Y. B. (Eds.) Molecular Mechanisms of Programmed Cell Death. Kluwer Academic/Plenum Publishers, New York 2003.
2. Shi YF, Liu CH, Roberts AI, Das J, Xu G, Ren G, Zhang Y, Zhang L, Yuan ZR, Tan HS, Das G, Devadas S. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don’t know. Interferons and cytokines. Shanghai Scientific & Technical Publishers. 2007.
3. Sengupta, S., Bhattacharya, G., Shaw, S., Hans, M., Devadas, S. (2022). Immunomodulation in Autoimmune Disorders. In: Kesharwani, R.K., Keservani, R.K., Sharma, A.K. (eds) Immunomodulators and Human Health. Springer, Singapore. https://doi.org/10.1007/978-981-16-6379-6_10

Lab in focus:

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