M tuberculosis in the Adjuvant Modulates Time of Appearance of CNS-Specific Effector T Cells in the Spleen through a Polymorphic Site of TLR2

Abstract

DC deliver information regulating trafficking of effector T cells along T-cell priming. However, the role of pathogen-derived motives in the regulation of movement of T cells has not been studied. We hereinafter report that amount of M tuberculosis in the adjuvant modulates relocation of PLP139-151 specific T cells. In the presence of a low dose of M tuberculosis in the adjuvant, T cells (detected by CDR3 BV-BJ spectratyping, the so-called “immunoscope”) mostly reach the spleen by day 28 after immunization (“late relocation”) in the SJL strain, whereas T cells reach the spleen by d 14 with a high dose of M tuberculosis (“early relocation”). The C57Bl/6 background confers a dominant “early relocation” phenotype to F1 (SJL×C57Bl/6) mice, allowing early relocation of T cells in the presence of low dose M tuberculosis. A single non-synonymous polymorphism of TLR2 is responsible for “early/late” relocation phenotype. Egress of T lymphocytes is regulated by TLR2 expressed on T cells. Thus, pathogens engaging TLR2 on T cells regulate directly T-cell trafficking, and polymorphisms of TLR2 condition T-cell trafficking upon a limiting concentration of ligand.

Toll-Like Receptor 2 Mediates In Vivo Pro- and Anti-inflammatory Effects of Mycobacterium Tuberculosis and Modulates Autoimmune Encephalomyelitis

“…F1 (SJL × B6 Tlr2− ) mice have a reduced Tlr2 gene dosage, and we have previously demonstrated that the lower gene dosage of these mice did not lead to a difference of TLR2 expression ( 30 ). To assess if the reduction of the EAE severity was a function of the higher gene dosage in F1 (SJL × B6 wt ) with respect to F1 (SJL × B6 Tlr2− ) mice, we induced EAE in littermates that were either F1 (SJL × B6 Tlr2− ) mice, having one copy of functional Tlr2 of SJL origin, or F1 (SJL × B6 ts ), having two copies of functional Tlr2 of SJL origin.…”

“…We have previously shown that the polymorphism of Tlr2 modulates T cell trafficking ( 30 ). Here, we have shown that each isoform of Tlr2 displayed a set of distinct pro- and anti-inflammatory properties with Tlr2 82ile promoting type 1/17 polarization and the expansion of antigen-specific FoxP3 + Tregs, and Tlr2 82met blocking the expansion of Tregs and that of production of IFN-γ and IL-17A.…”

“…This polymorphism affects the sensitivity to the amount of Mtb in the adjuvant, leading to differences in the mobilization of activated T cells from the lymph nodes (LNs). Tlr2 82met displays a dominant ability over Tlr2 82ile to promote early exit of antigen-specific T cells in the presence of limiting amounts of Mtb ( 30 ). While Tlr2 expressed on the APCs mediates most effects of the engagement of Tlr2 on the immune response, it is the engagement of Tlr2 expressed by the activated T cells that determines the early/late mobilization from LNs ( 30 ).…”

“…Our model based on a Tlr2 polymorphism allows to examine the role of Tlr2 in F1 (SJL × B6 wt ) mice having Tlr2 of both SJL (Tlr2 82ile ) and B6 (Tlr2 82met ), with Tlr2 82met dominant, as well as F1 [SJL × B6 129TLR2tm 1 kir/3 (B6 Tlr2− )] mice displaying only Tlr2 82ile of SJL origin ( 30 ). We have previously shown that the two F1 mice express similar Tlr2 levels on immune cells, despite having a different gene dosage.…”

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

“…EAE in the SJL mouse model: to induce active EAE, we immunized female SJL (8-10 week-old) mice, purchased from Charles River, with an emulsion composed by a fragment of the proteo-lipid protein (PLP139-151, the immunodominant epitope) and complete Freund's adjuvant (CFA4X) containing 4 mg of heat-killed and dried Mycobacterium tuberculosis (strain H37Ra, ATTC 25177, and Bordetella Pertussis toxin (Sigma-Aldrich S.r.l., Milan, Italy). Immunization and treatments are described in the timetable in Figure S1a, according to the procedures described in our previous works [14][15][16][17]. Mice have been monitored daily for body weight, development of clinical signs and symptoms (CSS), and for disease remission/relapse.…”