In this study, 22 PK patients with MVK or MVD variants were identified by targeted exome sequencing and exonic CNV screening. The distribution and cytokine production of peripheral T cells subsets were preliminary analyzed in those patients. It is well known that peripheral αβ T cells are primarily comprised of CD4+ T cells and CD8+T cells. Instead of directly staining CD4, we counted all CD3+Vδ1−Vδ2−CD8− cells as CD4+T cells. Besides the frequency of T cells subsets, we assessed the pro-inflammatory cytokines production by CD4+ T cells, CD8+ T cells, and Vγ9Vδ2 T cells in the peripheral blood. It was considered that the increases in percentages of peripheral CD4+ T cells were a secondary change, since the cytokines production by CD4+ T cells were unchanged in the PK patients with either MVK or MVD variants.
Different from the patients with MVK variants, we observed that there were significant decreases in percentages of both CD8+ and Vγ9Vδ2 T cells in the CD3+ T cells subsets in those with MVD variants. A possible explanation was that CD8+ and Vγ9Vδ2 T cells might home to the skin in the PK patients with MVD variants. An imbalance in the number and/or function of resident αβ and γδ T cells in the skin has been associated with chronic inflammation and skin-related diseases . A reduction in the number of peripheral γδT cells, along with the elevated numbers in the skin, has been reported in patients with psoriasis . As for non-conventional lymphocytes, human γδ T-cell acts as the first line of defense and bridge the innate and adaptive immune systems, representing < 5% of peripheral T-cell in the adult human peripheral blood. It is well established that multiple phosphorylated mevalonate metabolites are potent agonists of Vγ9Vδ2T cells . As the major peripheral γδ subsets, Vγ9Vδ2T cells are dually regulated by intracellular and extracellular mevalonate metabolism. Moreover, the peripheral Vγ9Vδ2 T cells from PK patients with MVD variants showed a higher proportion expressed TNF-α compared with NCs. In a different way, the dysregulated secretion of IFN-γ by CD8 + T cells were observed in the PK patients with MVK variants. It is noteworthy that the IFN-γ signaling for CD8+ T cells differentiation are delivered early in the immune response. The autocrine IFN-γ signaling plays an important role in Th1 differentiation and CD8+ T cells cross-priming [10, 12, 13]. It suggested that autoreactive CD8+ and γδ T cells might play a critical role in the skin-specific autoinflammatory PK. However, it was not known to what extent, if any, the pro-inflammatory effects of these T cells might affect the pathogenesis of PK.
Danger signals from exogenous pathogens and endogenous keratinocyte death might trigger skin inflammation [14, 15]. Under certain circumstances, genetic defects in mevalonate pathway might block DNA degradation during epidermal cornification and develop a vertical “column” of parakeratosis, histologically defined as a cornoid lamella (CL). In the context of a heterogeneous group of disease, CL unifies all phenotypes of PK. It is remarkable that non-specific papillary dermal lymphocytic infiltration are frequently seen under the CL [16,17]. The local immune cell infiltration and chronic activation are involved in the pathomechanisms of PK . The limitations of this study include a small sample size and the lack of comparison of CD8+T and γδT cells in the lesions of PK with MVK or MVD variants. Further investigation is under way to explore T cells in the lesions of PK.
Taken together, our findings showed alterations in peripheral T-cell subsets in PK patients and provided the cues to further studies on autoreactive CD8 + T and γδT cells in the pathogenesis of autoinflammatory keratinization.