Regulation of key molecules of immunological synapse by T11TS immunotherapy abrogates Cryptococcus neoformans infection in rats

• Published in: Molecular immunology Vol. 122; pp. 207 - 221
• Main Authors: Sk Md, Omar Faruk, Hazra, Iman, Datta, Ankur, Mondal, Somnath, Moitra, Saibal, Chaudhuri, Suhnrita, Das, Prasanta Kumar, Basu, Anjan Kumar, Mishra, Roshnara, Chaudhuri, Swapna
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2020
• Subjects: Cryptococcus neoformans; Immunological synapse; Immunotherapy; Macrophage; RANTES; T cell; T11 target structure (T11TS); Immunological synapse; T11 target structure (T11TS); Cryptococcus neoformans; RANTES; Immunotherapy; T cell; Macrophage
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2020.04.021

Proposed mode of action of T11TS on the Immunological Synapse of T cell and Macrophages in C. neoformans infected rats. Immunological Synapse molecules such as TCRαβ, CD3ζ, CD2, CD4, CD8, CD28, CTLA-4, CD45 on T cells and MHC I, MHC II, CD80 on macrophages were repressed by C. neoformans infection. The immune-potentiator T11TS activates the above Immunological Synapse molecules with down-regulation of inhibitory CTLA-4 to facilitate the initiation signaling pathway in T cells. These molecules help in channelization of the downstream signaling in T cell. [Display omitted] •Preclinical immunotherapy with T11TS in cryptococcosis in the rat model.•Enhanced clearance of fungus from the lung tissue in the T11TS treated groups.•Improved RANTES level in the T11TS treated groups suggests recruitment of T cells.•Immunological Synapse modulation in cryptococcosis and after T11TS treatment. 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.