Abstract
Dysregulated cytokine expression by T cells plays a pivotal role in the pathogenesis of autoimmune diseases. However, the identification of the corresponding pathogenic subpopulations is a challenge, since a distinction between physiological variation and a new quality in the expression of protein markers requires combinatorial evaluation. Here, we were able to identify a super-functional follicular helper T cell (Tfh)-like subpopulation in lupus-prone NZBxW mice with our binning approach "pattern recognition of immune cells (PRI)". PRI uncovered a subpopulation of IL-21+ IFN-γhigh PD-1low CD40Lhigh CXCR5- Bcl-6- T cells specifically expanded in diseased mice. In addition, these cells express high levels of TNF-α and IL-2, and provide B cell help for IgG production in an IL-21 and CD40L dependent manner. This super-functional T cell subset might be a superior driver of autoimmune processes due to a polyfunctional and high cytokine expression combined with Tfh-like properties.
Highlights
CD4 T cells play a major role in autoimmune diseases such as systemic lupus erythematosus (SLE) by accumulating as autoreactive disease-promoting memory cells and amplifying inflammation as well as providing B cell help (Suarez-Fueyo et al, 2016)
We calculated and depicted the features (i) cell density, (ii) frequency of IFN-g-producing cells (%), (iii) mean fluorescence intensity (MFI) of IFN-g, and (iv) the relative expression level of IFN-g calculated as mean fluorescence intensity of IFN-g only of IFN-g+ cells (MFI+ (IFN-g)) (Figure 1F)
As loss of poly-functionality is considered as a hallmark of chronic infections and often used as an end-point to evaluate exhaustion of CD8+ and CD4+ T cells (Larsen et al, 2012; Tilstra et al, 2018), we investigated the combinatorial expression of the four cytokines with PD-1
Summary
CD4 T cells play a major role in autoimmune diseases such as systemic lupus erythematosus (SLE) by accumulating as autoreactive disease-promoting memory cells and amplifying inflammation as well as providing B cell help (Suarez-Fueyo et al, 2016). Of particular interest are the recently observed human T peripheral helper cells (Tph), which expand in autoimmune diseases (Bocharnikov et al, 2019; Christophersen et al, 2019; Ekman et al, 2019; Rao et al, 2017). These and other studies show on the one hand the enormous potential to gain new biological insights from multidimensional cytometry data.
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