The soluble cytoplasmic tail of CD45 (ct-CD45) is a cleavage fragment of CD45, that is generated during the activation of human phagocytes. Upon release to the extracellular space, ct-CD45 binds to human T cells and inhibits their activation in vitro. Here, we studied the potential role of TLR4 as a receptor for ct-CD45. Treatment of Jurkat TLR4/CD14 reporter cells with ct-CD45 induced the upregulation of the reporter gene NFκB-eGFP and could be blocked by inhibitors of TLR4 signaling. Conversely, ct-CD45 did not promote the NFκB-controlled eGFP induction in reporter cells expressing TLR1, TLR2, and TLR6 transgenes and did not lead to the activation of the transcription factors NFκB, AP-1, and NFAT in a Jurkat reporter cell line expressing endogenous TLR5. Moreover, ct-CD45 binds to recombinant TLR4 in an in vitro assay and this association was reduced in the presence of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine. Blockade of TLR4 with mAb HTA125 partially reversed the ct-CD45-mediated inhibition of T-cell proliferation. Interestingly, targeting of TLR4 with mAb W7C11 also suppressed T-cell proliferation. In summary, the results of this study demonstrate that ct-CD45 acts via a noncanonical TLR4 activation pathway on T cells, which modulates TCR signaling.

Targeting of the pro-inflammatory cytokines interleukin 17A (IL-17A) or tumor necrosis factor alpha (TNFα) with monoclonal antibodies (mAbs) ixekizumab or adalimumab, respectively, are successful therapies in chronic plaque psoriasis. The effects of these treatments on immune cell populations in the skin are largely unknown. In this study, we compared the composition of cutaneous, lesional as well as non-lesional, and blood immune cells in ixekizumab or adalimumab treated patients with psoriasis. Our data reveal that both treatments efficiently down-regulate T-cells, macrophages and different subsets of dendritic cells (DCs) in lesional skin towards levels of healthy skin. In contrast to lesional skin, non-lesional areas in patients harbor only few or no detectable DCs compared to skin of healthy subjects. Neither the treatment with ixekizumab nor adalimumab reverted this DC imbalance in non-lesonal skin of psoriatic patients. Taken together, our study shows that anti-IL-17A as well as anti-TNFα therapy rebalances the immune cell repertoire of lesional skin in psoriatic patients, but fail to restore the disturbed immune cell repertoire in non-lesional skin during the induction phase of therapy.

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