Opposing effects of actin signaling and LFA‐1 on establishing the affinity threshold for inducing effector T‐cell responses in mice. Issue 8 (8th June 2016)

• Record Type: Journal Article
• Authors: Palmer, Ed; Drobek, Ales; Stepanek, Ondrej
• Is Part Of: European journal of immunology. Volume 46:Issue 8(2016)
• Page Start: 1887
• Page End: 1901
• Publication Date: 2016-06-08
• Subjects: Actin cytoskeleton -- Antigen affinity threshold -- LFA‐1 -- Rap1 -- Rho‐family GTPases -- T‐cell receptor signaling; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201545909
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract : T cells discriminate between high‐affinity foreign antigens and low‐affinity self‐antigens. Only high‐affinity TCR antigens induce substantial rearrangement of actin microfilaments toward the immunological synapse, which results in the amplification of the TCR signals induced by these antigens. In contrast, LFA‐1:ICAM‐1 interaction enhances signaling induced by both low‐ and high‐affinity antigens. Abstract : Mature CD8 + T cells use a narrow antigen affinity threshold to generate tissue‐infiltrating cytotoxic effector T cells and induce autoimmune pathology, but the mechanisms that establish this antigen affinity threshold are poorly understood. Only antigens with affinities above the threshold induce stable contacts with APCs, polarization of a T cell, and asymmetric T‐cell division. Previously published data indicate that LFA‐1 inside‐out signaling might be involved in establishing the antigen affinity threshold. Here, we show that subthreshold antigens weakly activate all major distal TCR signaling pathways. Low‐affinity antigens are more dependent on LFA‐1 than suprathreshold antigens. Moreover, augmenting the inside‐out signaling by hyperactive Rap1 does not increase responses to the subthreshold antigens. Thus, LFA‐1 signaling does not contribute to the affinity‐based antigen discrimination. However, we found that subthreshold antigens do not induce actin rearrangement toward an APC, mediated by Rho‐family GTPases, Cdc42, and Rac. Our data suggest that Rac and Cdc42 contribute to the establishment of the antigen affinity threshold in CD8 + T cells by enhancing responses to high‐affinity antigens, or by reducing the responses to low‐affinity antigens.