5.2.2. γδT Cells

γδT cells, a subset of T cells that expresses γδTCR, account for a minor portion (3–5%) of all circulating T cells, but they are much more prevalent at mucosal and epithelial sites, where they account for approximately 50% of the intraepithelial lymphocyte population [76]. γδT cells play an important role in the mucosal defense against bacterial infection and antitumor immunity [77,78]. Among them, a subset of IL-17-producing γδT cells also play an especially pathological role in SpA [79]. In Ps patients, dermal γδT cells that produce IL-17 in response to IL-23 were increased in the affected skin, leading to disease progression [80,81]. In addition, the enrichment of circulating IL-17-secreting γδT cells was identified in patients with PsA and AS [82,83]. Cuthbert et al. identified tissue-resident γδT cells in the spinal enthesis, which were divided into two subsets: Vδ1 and Vδ2. While Vδ2 cells expressed IL-23/IL-17 axis-associated transcripts including IL-23R, Vδ1 completely lacked IL-23R expression and produced IL-17 in an IL-23-independent manner [84].

#### 5.2.3. Mucosa-Associated Invariant T (MAIT) Cells

Mucosal-associated invariant T (MAIT) cells are one of the subsets of innate-like cells, abundantly enriched in mucosal tissue, liver, and blood. MAIT cells act at the intersection of the innate and adaptive immune system and play an important role against bacterial infections. MAIT cells express the TCR αchain, and their activation depends on a restriction by a nonpolymorphic MHC-related molecule-1 (MR1) [85]. Through MR1 activation, MAIT cells produce pro-inflammatory cytokines such as IL-17, IL-22, and IFN-γ. Recent evidence has indicated the involvement of MAIT cells in the derivation of IL-17 in the Spondyloarthritis. IL-17-producing CD8+ MAIT cells were identified in psoriatic skin and blood in Ps patients [86] and were also identified in the synovial fluid in patients with PsA [72]. In addition, MAIT cells were found to be involved in AS. Although the frequency of circulating MAIT cells was lower than in healthy controls, the proportion of IL-17+ MAIT cells in the blood of patients with AS was elevated [87–89]. Higher proportions of MAIT cells were found in the synovial fluid than in the circulation. Hayashi et al. also demonstrated the correlation between the expression of CD69 on MAIT cells with the Ankylosing Spondylitis Disease Activity Score (ASDAS) in patients with AS. These results suggest that the upregulation of IL-17 by MAIT cells contributes to the pathogenesis of SpA.

#### 5.2.4. Type 3 Innate Lymphoid Cells (ILC3)

Innate lymphoid cells (ILCs) are immune cells that belong to the family of lymphoid effector cells and that play a pivotal role in immune defense, inflammation, and tissue remodeling [90]. ILCs are divided into three lineages based on their distinct production of cytokines: ILC1 produces IFN-γ; ILC2 is the predominant source of IL-4, IL-5, and IL-9; and ILC3 produces IL-17 and IL-22 in response to IL-23 [91].

Increased levels of IL-17-producing ILC3s, a lineage-negative cell population, have been identified in the peripheral blood of patients with PsA compared with healthy controls, and the levels of ILC3 correlated with the disease activity [92]. In AS patients, Cuthbert et al. identified ILC3s in the human enthesis [93] and Ciccia et al. demonstrated that gut-derived IL-17-producing ILC3s were expanded in the peripheral blood and synovial fluid [48].
