Page 45 - GTM-2-1

Global Translational Medicine Inflammatory and anti-inflammatory responses in HTLV1

and production of potent tolerogenic cytokines, such
as interleukin (IL)-10, IL-35, and transforming growth
factor beta (TGF-β) . Therefore, Tregs can modulate
[17]
the adverse immune responses that may be involved in
the pathogenesis of HTLV-1 infection [18,19] . TGF-β plays a
regulatory role in establishing and maintaining peripheral
and tissue tolerance [20,21] . IL-10, as a multifunctional
cytokine, can effectively limit adverse inflammatory
response [20,21] . In addition, IL-10 is also essential for
immune homeostasis [20,21] . IL-35 is an inhibitory cytokine
composed of Epstein-Barr virus-induced gene 3 and p35
subunits released by Tregs . IL-35 appears to play a
[22]
critical role in infectious tolerance not only by suppressing
the proliferation of effector T cells, but also by inducing
the production of IL-35 by non-FOXP3 conventional T
[23]
cells (Tconvs), which areknown as iTr35 cells . IL-35
has also been associated with the suppression of various
Figure 1. Cellular mechanisms underlying the pathogenesis of human autoimmune diseases and atherosclerosis [23,24] .
T-lymphotropic virus type 1-associated myelopathy/tropical spastic
paraparesis (HAM/TSP). HTLV-1-specific immune responses and 3. T-helper 17 cells
secondary inflammations inflated in the CNS may lead to subsequent CNS +
damage. CNS, central nervous system; HTLV-1, human T-lymphotropic Th17 cells are the subpopulation of CD4 T cells, with
virus Type 1; HTLV-1. a pro-inflammatory cytokine profile, including IL-21,
★
IL-22, IL-17A, IL-17 F, and tumor necrosis factor alpha
interactions between viral envelope (Env) glycoproteins, a (TNFα) [25-28] . Retinoicacidreceptor-related orphan
surface glycoprotein (SU) and a transmembrane glycoprotein nuclear receptor gammat (ROR-γt) is the most important
(TM), with specific cell surface molecules, referred to as transcription factor involved in Th17 cell differentiation
[29]
receptors. SU is involved in receptor recognition, while TM and function . The N terminus of RORγt has a
triggers the fusion of viral and cellular membranes, allowing transcription modulation domain (TMD) comprising
viral particles to enter target cells [9,10] . GLUT1 has been deoxyribonucleic acid(DNA)-binding amino acid residues
shown to specifically bind to a truncated soluble form of and isotype-specific sequences that may play key roles in
[30]
HTLV-1 and HTLV-2 SU proteins, and the level of GLUT1 the functional specificity of RORγt . RORγt, induced
in target cells has been found to be correlated with the titer at the early stage of Th17 cell differentiation following
of HTLV-2 Env-pseudotyped virus [10,11] . HSPGs might IL-6 and TGF-β stimulation, has a pivotal role inTh17
[31]
play a role in HTLV-1 entry. T-helper 17 (Th17) cells and cell lineage commitment . RORγt specifically binds
regulatory T cells (Tregs) are two subsets of CD4 T cells . to and regulates Th17-associated genes, such asIL17A,
[12]
+
IL17F, andIL23R, by activating their transcription in
[32]
2. Regulatory T cells coordination with other transcription factors . Therefore,
targeting RORγt by small molecules either genetically
Tregs are a subpopulation of CD4 T cells . Tregs have or pharmacologically is effective in ameliorating Th17-
+
[13]
multiple markers, including CD25, glucocorticoid-induced related inflammatory disorders, including experimental
tumor necrosis factor receptor family-related protein(GITR), autoimmune encephalomyelitis (EAE), psoriasis, arthritis,
CD45R, CD62L, CD127, CD103, cytotoxic Tlymphocyte colitis, and glomerulonephritis, especially in preventative
antigen-4 (CTLA-4), and programmed cell death 1 (PD-1) disease models .
[33]
[14] . Forkhead box P3 (FOXP3) is a master transcription
factor of Tregs that plays a key role in Tregs activity . IL-17A is responsible for inducing cell types to produce
[15]
other pro-inflammatory cytokines, chemokines, and
Tregs have shown to be useful for immunotherapy metalloproteinases, thereby recruiting neutrophils to the
in autoimmune and inflammatory conditions as they tissue and contributing to the inflammation process .
[34]
contribute to establishing and maintaining immune IL-22 is a key cytokine produced by Th17 cells, and it
homeostasis [12,16] . Tregs can regulate innate immune cells plays an important role in maintaining homeostasis and
and adaptive immune cells as well as suppress adverse remodeling epithelial tissues. The importance of IL-22
inflammatory responses of both T and B cells in adaptive has been highlighted in the pathogenesis of psoriasis [35,36] .
immunity. The functions of Tregs include cell contact In a study, IL-22 mRNA expression was found to be

Volume 2 Issue 1 (2023) 2 https://doi.org/10.36922/gtm.v2i1.67