Superantigen-induced CD4 memory T cell anergy. I. Staphylococcal enterotoxin B induces Fyn-mediated negative signaling

Abstract

Memory CD4 T cells must provide robust protection for an organism while still maintaining self-tolerance. Superantigens reveal a memory cell-specific regulatory pathway, by which signaling through the TCR can lead to clonal tolerance (anergy). Here we show that the src kinase Fyn is a critical regulator of anergy in murine memory CD4 T cells induced by the bacterial superantigen staphylococcal enterotoxin B (SEB). Exposure to SEB results in impaired TCR signaling due to failed CD3/ZAP-70 complex formation. Further, signal transduction through the TCR remains similarly blocked when anergic memory cells are subsequently exposed to agonist peptide antigen. Pharmacological inhibition or genetic elimination of Fyn kinase reverses memory cell anergy, resulting in SEB-induced cell proliferation. The mechanism underlying impaired TCR signaling and subsequent memory cell anergy must involve a Fyn signaling pathway given that the suppression of Fyn activity restores CD3/ZAP-70 complex formation and TCR proximal signaling.

Anergy in CD4 memory T lymphocytes. II. Abrogation of TCR-induced formation of membrane signaling complexes

“…The expression of the clonotypic, KJ1-26, TCR allowed these cells to bind to either the OVA peptide or SEB. We have previously discussed the OVA-specific memory cells from these mice [26;33;28]. Of relevance to the current study, we extended our observations, originally made using non-transgenic memory cells [40;41], and showed that DO11.10 memory CD4 T cells were also hyporesponsive to SEB [26].…”

“…Both the initial failure to proliferate and subsequent anergy were due to impaired TCR proximal signaling, characterized by a failure of ZAP-70 to bind to the TCR/CD3 complex [7]. The lack of response to SEB was dependent upon Fyn activation as the absence of Fyn led to SEB-induced memory cell proliferation ([28] and Figure 1). …”

“…Further, the inhibition or absence of Fyn kinase is able to restore memory cell proliferation and prevent anergy [28]. Immunoblot studies showed that when Fyn was absent, complexes of pZAP-70 and CD3ζ could be precipitated from memory cells exposed to SEB [28].…”

“…Hence, there was an absence of tyrosine phosphorylation of ZAP-70 and further downstream signaling was blocked. Additional studies showed that a specific hyperactivation of the src kinase Fyn was essential to SEB-induced memory cell anergy, as the inhibition or absence of Fyn restored both CD3ζ/ZAP-70 complex formation and cell activation [28]. …”

Superantigens Subvert the Neutrophil Response To Promote Abscess Formation and Enhance Staphylococcus aureus SurvivalIn Vivo

“…Indeed, an inability to form neutralizing antibodies has been linked to many cases of TSS (11,79); however, SAgs also are highly immunogenic, and the majority of the population is able to form both anti-SAg and anti-staphylococcal antibodies (80). Although purified SAgs have long been shown to induce T cell anergy (81)(82)(83)(84), to our knowledge, the role of SAg-mediated T cell anergy has not been demonstrated during a live infection. In our model, SEA-expressing S. aureus caused a decrease in the detectable V␤3 ϩ CD3 ϩ cells, although SAg-activated T cells usually undergo early expansion (85,86).…”