Regulatory Rheumatoid Factor is Specific to PD-1 and Uses PD-1 Pathway to Control CD4 T Lymphocytes

We have earlier discovered a new factor of autoimmunity downregulation, called regulatory rheumatoid factor (regRF). Being anti-idiotypic antibodies, regRF restricts the expansion of CD4⁺ T lymphocytes to the idiotype of which it is specific, according to the negative feedback principle. It has been shown that only activated CD4⁺ T lymphocytes are the target of regRF. However, it is still not clear the way regRF distinguishes activated cells from naive ones. RegRF molecules, apart from individual paratopes specific to unique sequences of B- and T-cell receptors, have a shared paratope. We assume that regRF by means of a shared paratope recognizes one of the surface activation molecules of CD4⁺ T lymphocytes and initiates the cell death. Programmed death-1 (PD-1) has been tested as a potential receptor of the shared regRF paratope and transmitter of the negative regRF signal into activated CD4⁺ T lymphocytes.

The specificity of the shared regRF paratope to PD-1 was determined by ELISA. T cell activation was performed with immobilized anti-CD3ε antibodies. Flow cytometry was used to study the effect of regRF on PD-1⁺CD4⁺ lymphocytes.

We found that regRF binds to PD-1. IgG Fc fragments carrying epitopes specific to the shared paratope of regRF compete with PD-1 for binding to regRF. It follows that regRF recognizes specifically PD-1 by means of a shared paratope. RegRF-containing serum reduced the number of PD-1⁺CD4⁺ lymphocytes in proportion to their increase resulting from the action of anti-CD3ε antibodies.

RegRF uses PD-1 pathway to control activated CD4⁺ T lymphocytes.