C-Reactive Protein Directly Suppresses Th1 Cell Differentiation and Alleviates Experimental Autoimmune Encephalomyelitis

Abstract

Human C-reactive protein (CRP) is a serum soluble pattern recognition receptor (PRR) that serves as a marker of inflammation and directly contributes to innate immunity. Herein we show that human CRP also directly contributes to adaptive immunity, i.e. native CRP binds specifically to human Jurkat T cells and to mouse naïve CD4+ T cells and modulates their T helper (Th) 1 and Th2 responses. In vitro both exogenously added (purified) and endogenously expressed (via transfection) human CRP inhibited Th1 differentiation and augmented Th2 differentiation of naïve CD4+ T cells. In vivo for human CRP transgenic (CRPtg) compared to wild type mice, a lesser proportion of the T cells recovered from the spleens of healthy animals were Th1 cells. Moreover in both CRPtg mice and in wild type mice treated with human CRP, during myelin oligodendrocyte glycoprotein peptide induced experimental autoimmune encephalomyelitis both the Th1 cell response and disease severity were inhibited. These pattern recognition-independent actions of CRP directly on T cells highlights the potential for this soluble PRR to act as a tonic regulator of immunity, shaping global adaptive immune responses during both homeostasis and disease.

Plasma Levels of Endothelial Microparticles Bearing Monomeric C-reactive Protein are Increased in Peripheral Artery Disease

“…Our studies suggest that specific isoforms of CRP mediate chronic inflammation, in part, by modulating the polarization of monocytes and T lymphocytes migrating across the endothelial layer. Recently, it has been reported that CRP (untested for isoform content) directly stimulated Th2 polarization of the human Jurkat T cell line [38], and here we report that pCRP promoted a Th2 response with M2 macrophage differentiation, whereas mCRP promoted a Th1 response with M1 macrophage differentiation. By logical extension, the effect of CRP isoforms on T lymphocytes in the progression of atherosclerotic plaques presents a promising potential area of study.…”

Phosphocholine‐containing ligands direct CRP induction of M2 macrophage polarization independent of T cell polarization: Implication for chronic inflammatory states

“…What is surprising is that CRP could shift the monocyte response to an M2 phenotype without affecting that T cell response. M2 macrophages have been observed to direct T cell activation and maturation , and so we expected a change from a Th1 to a Th2 response in cultures with CRP, especially since CRP has been reported to suppress Th1 cell differentiation . Others have shown that oxidized lipids induce maturation of naïve T cells to Th1 cells ; thus it is possible that the Th1 response could become chronic or predominant based on continuous recruitment of new cells to a proinflammatory phenotype (Fig.…”

An Intrinsically Disordered Motif Mediates Diverse Actions of Monomeric C-reactive Protein

“…With the aid of crystal structure, a specific inhibitor blocking the binding of pentameric CRP to phosphorylcholine has been developed showing beneficial effects in a rat model undergoing acute myocardial infarction (49). However, given the putative function of CRP in host defense (50) and its (tonic and global) anti-inflammatory activities (4,51), the systemic long-term inhibition appears to be problematic. mCRP may be the functionally dominant conformation of CRP active in inflammatory loci (3)(4)(5).…”