Inhibition of T-cell activity in alopecia areata: recent developments and new directions

Abstract

Alopecia areata (AA) is an autoimmune disease that has a complex underlying immunopathogenesis characterized by nonscarring hair loss ranging from small bald patches to complete loss of scalp, face, and/or body hair. Although the etiopathogenesis of AA has not yet been fully characterized, immune privilege collapse at the hair follicle (HF) followed by T-cell receptor recognition of exposed HF autoantigens by autoreactive cytotoxic CD8⁺ T cells is now understood to play a central role. Few treatment options are available, with the Janus kinase (JAK) 1/2 inhibitor baricitinib (2022) and the selective JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor ritlecitinib (2023) being the only US Food and Drug Administration-approved systemic medications thus far for severe AA. Several other treatments are used off-label with limited efficacy and/or suboptimal safety and tolerability. With an increased understanding of the T-cell-mediated autoimmune and inflammatory pathogenesis of AA, additional therapeutic pathways beyond JAK inhibition are currently under investigation for the development of AA therapies. This narrative review presents a detailed overview about the role of T cells and T-cell-signaling pathways in the pathogenesis of AA, with a focus on those pathways targeted by drugs in clinical development for the treatment of AA. A detailed summary of new drugs targeting these pathways with expert commentary on future directions for AA drug development and the importance of targeting multiple T-cell-signaling pathways is also provided in this review.

Keywords: Alopecia areata; JAK inhibitor; T cells; T-cell receptor; autoimmune disease.

Figure 1

Mechanism of Action of T-Cell Signaling in AA and Inhibitors Targeting Key Pathways. AA, alopecia areata; CD, cluster of differentiation; CXCL10, C-X-C motif chemokine ligand 10; HF, hair follicle; IFN, interferon; IL, interleukin; ILT7, leukocyte immunoglobulin-like receptor subfamily A member 4; ITK, interleukin-2–inducible T-cell kinase; JAK, Janus kinase; MHC, major histocompatibility complex; NKG2D(L), natural killer group 2 member D (ligand); pDC, plasmacytoid dendritic cell; S1P, sphingosine-1-phosphate; TCR, T-cell receptor; TYK2, tyrosine kinase 2. ^a ILT7 is activated by bone marrow stromal cell antigen 2 (BST2), a surface-expressed protein upregulated in cells exposed to INF-α, leading to a negative feedback loop resulting in restricted production of INF-α by pDCs (63). ^b Inhibition of TYK2 by deucravacitinib also inhibits differentiation of T cells via pDC-derived IL-23. ^c EQ101 (formerly known as BNZ-I) also inhibits IL-2 and IL-9 signaling.

Figure 2

Summary of JAK/STAT Signaling Pathways. (A) IL receptor-JAK protein configurations. (B) Canonical JAK/STAT signaling mechanism: (1) the cytokine binds to and induces association of receptor subunits; (2) receptor-associated JAKs become phosphorylated and subsequently phosphorylate the intracellular tail of the cytokine receptor; (3) phosphorylation allows docking of STATs to the receptors, where they become phosphorylated; and (4) phosphorylated STATs dimerize and translocate to the nucleus, where they regulate downstream transcription of inflammatory factors. EPO, erythropoietin; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; JAK, Janus kinase; NK, natural killer; STAT, signal transducer and activator of transcription; TPO, thrombopoietin; Th, T helper cell; TYK, nonreceptor tyrosine kinase.

Figure 3

Overview of TCR Signaling Cascade in CD8⁺NKG2D⁺ T Cells. APC, antigen-presenting cell; Ca, calcium; CD, cluster of differentiation; DAG, diacylglycerol; IP₃, inositol-1,4,5-triphosphate; ITK, interleukin-2–inducible T-cell kinase; LAT, linker for activation of T cells; LCK, lymphocyte-specific protein tyrosine kinase; MHC, major histocompatibility complex; NKG2D, natural killer group 2 member D; PIP₂, phosphatidylinositol 4,5-bisphosphate; PIP₃, phosphatidylinositol-3, 4, 5-triphosphate; PKC, protein kinase C; PLCγ, phospholipase C γ; SLP76, SRC-homology-2-domain-containing leukocyte protein of 76 kDa; TCR, T-cell receptor; ZAP70, zeta chain–associated protein kinase 70.