Importance of TCR ITAM multiplicity in the establishment of central tolerance (36.48)

Abstract

Abstract Thymocyte selection is controlled by signaling motifs (ITAMs) contained within the invariant T cell receptor (TCR) subunits. The current model of thymocyte selection posits that differences in the affinity of the TCR for self-peptides results in differences in the TCR signaling response, with low affinity interactions promoting positive selection and high affinity interactions triggering negative selection. We and others previously demonstrated that attenuation of TCR signaling potential (by mutation of the zeta chain ITAMs) leads to the generation of T cells that express auto-reactive TCRs. However, these T cells did not cause autoimmune disease, presumably because TCR/self-peptide interactions do not induce strong effector responses in the absence of zeta ITAMs. This paradigm was recently challenged in a study reporting that retroviral reconstitution of zeta deficient bone marrow with ITAM mutant zeta chains results in fatal autoimmune disease. In the current study, we generated a knock-in (KI) mutation at the zeta locus that results in expression of a zeta chain where each of the ITAM tyrosines is mutated to phenylalanine (6YF). The phenotype of zeta-6YF mice demonstrates that attenuation of TCR signaling potential is not, by itself, sufficient to abrogate central tolerance. In addition, our results confirm that the threshold for T cell activation is determined by both the affinity of the TCR and by the TCR signaling potential