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Regulation of key molecules of immunological synapse by T11TS immunotherapy abrogates Cryptococcus neoformans
Omar Faruk Sk Md1, Iman Hazra2, Ankur Datta2
1Department of Laboratory Medicine, School of Tropical Medicine, 108, C. R. Avenue, Kolkata 700073, West Bengal, India; Department of Physiology, University of Calcutta, 92 A.P.C. Road, Kolkata 700009, India.
Abstract:
Cryptococcus neoformans infects and disseminates in hosts with diminished T cell responses. The immunomodulator T11TS (T11 target structure) had profound potential in glioma as well as C. neoformans infected model for disease amelioration. It is been established by our group that T11TS potentiates Calcineurin-NFAT pathway in T cells of C. neoformans infected rats. We investigated the upstream Immunological Synapse (IS) molecules that are vital for the foundation of initial signals for downstream signaling, differentiation and proliferation in T cells. Improved RANTES level in the T11TS treated groups suggests potential recruitment of T cells. Down-regulation of TCRαβ, CD3ζ, CD2, CD45 and CD28 molecules by cryptococcus were boosted after T11TS therapy. Heightened expression of inhibitory molecule CTLA-4 in cryptococcosis was dampened by T11TS. The decline of MHC I, MHC II and CD80 expression on macrophages by C. neoformans were enhanced by T11TS. The dampening of positive regulators and upsurge of negative regulators of the IS during cryptococcosis was reversed with T11TS therapy resulting in enhanced clearance of fungus from the lungs as envisaged by our histological studies. This preclinical study with T11TS opens a new prospect for potential immunotherapeutic intervention against the devastating C. neoformans infection with positive aspect for the long-term solution and a safer immunotherapeutic regimen.
Insights
The immunomodulator T11 target structure (T11TS) therapy reversed immune suppression caused by Cryptococcus neoformans infection. T11TS enhanced T cell function and fungal clearance, offering a promising new treatment.
Area of Science:
- Immunology
- Microbiology
- Pharmacology
Background:
- Cryptococcus neoformans infection primarily affects individuals with compromised T cell immunity.
- The immunomodulator T11 target structure (T11TS) has shown potential in treating glioma and C. neoformans infections.
- T11TS is known to potentiate the Calcineurin-NFAT pathway in T cells during C. neoformans infection.
Purpose of the Study:
- To investigate the upstream Immunological Synapse (IS) molecules affected by T11TS therapy in a C. neoformans infection model.
- To understand how T11TS influences T cell signaling, differentiation, and proliferation in the context of cryptococcosis.
- To evaluate the therapeutic potential of T11TS for ameliorating C. neoformans-induced disease.
Main Methods:
- Analysis of T cell surface molecules (TCRαβ, CD3ζ, CD2, CD45, CD28, CTLA-4) and macrophage markers (MHC I, MHC II, CD80) via flow cytometry.
- Measurement of chemokine levels (RANTES) to assess immune cell recruitment.
- Histological examination of lung tissue to evaluate fungal burden and tissue damage.
Main Results:
- T11TS therapy increased RANTES levels, suggesting enhanced T cell recruitment.
- T11TS reversed the down-regulation of key T cell molecules (TCRαβ, CD3ζ, CD2, CD45, CD28) and the up-regulation of inhibitory CTLA-4 induced by C. neoformans.
- T11TS enhanced the expression of MHC I, MHC II, and CD80 on macrophages, counteracting the suppressive effects of the fungus.
- Histological analysis confirmed improved fungal clearance in T11TS-treated groups.
Conclusions:
- T11TS therapy effectively reverses the immunosuppressive effects of C. neoformans by modulating the Immunological Synapse.
- This preclinical study demonstrates T11TS as a potential immunotherapeutic agent for C. neoformans infections, promoting fungal clearance and immune restoration.
- T11TS offers a promising, safer, and potentially long-term solution for managing cryptococcosis.
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