The immunosuppressive effect of the tick salivary protein, Salp15, is persistent and has long-term effects in a murine model of hematopoietic transplant

Salp15, a salivary protein of Ixodes ticks, inhibits the activation of naïve CD4 T cells. Treatment with Salp15 results in immunomodulation in different murine models in which these cells participate. The fate of the CD4 T cells activated in the presence of the immunosuppressor or its long-term effects on these cells are however, unknown. We now show that Salp15 binding to CD4 is persistent and induces a long-lasting immunomodulatory effect. The activity of Salp15 results in sustained diminished antibody production against specific and unrelated antigens. Transcriptionally, the salivary protein provokes a sharp acute effect that includes known activation factors, such as Il2, Cd44, or Il2ra, and that fades over time. The long-term effects exerted by Salp15 do not involve the induction of either anergy traits nor increased populations of regulatory T cells. Similarly, the treatment with the immunomodulatory protein does not result in B cell anergy or the generation of myeloid suppressor cells. However, the immunomodulatory protein induces the increased expression of the ectoenzyme, CD73, in regulatory T cells. Our results suggest that the specific regulation of CD73, a known modulator of adenosine levels, by Salp15 results in long-term cross-antigenic immunomodulatory effects. Overall design: Genome-wide changes in gene Expression in mouse CD4 T cells activated with anti-CD3/CD28 in the presence of 25 ug/mL of the tick salivary protein, Salp15 or its inactive control (Salp15deltaP11) were generated by RNAseq.

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Tomás-Cortázar J, Martín-Ruiz I, Barriales D, Pascual-Itoiz MÁ, de Juan VG, Caro-Maldonado A, Merino N, Marina A, Blanco FJ, Flores JM, Sutherland JD, Barrio R, Rojas A, Martínez-Chantar ML, Carracedo A, Simó C, García-Cañas V, Abecia L, Lavín JL, Aransay AM, Rodríguez H, Anguita J