T cells play a central role in mediating adaptive immune responses (Chang et al., 2014, Jameson and Masopust, 2018, Jarjour et al., 2021). The differentiation and effector responses of T cells is triggered upon engagement of T cell receptor (TCR) with cognate antigens presented by the major histocompatibility complex of antigen-presenting cells (APC) (Gaud et al., 2018, Shah et al., 2021). The cognate recognition of antigens by TCR thus confines T cell responses to a very limited clonotypes, which underlies the tight specificity of adaptive immunity. Nevertheless, recent studies have also demonstrated a cognate antigen-independent polyclonal activation of T cells induced by cytokines released from innate immune cells or ligands of TLR2 or TLR4, membrane-integrated pattern recognition receptors (PRR) of the innate immune system (Lee et al., 2022). Such a bystander T cell activation does not rely on TCR signaling, and can, in principle, contribute to mounting an early adaptive immune response shortly after the activation of innate immune responses. This could confer immediate host protection against previously unencountered pathogens, but may also cause immunopathological injury to the host (Lee et al., 2020; Whiteside et al., 2018).

C-reactive protein (CRP) is a major acute phase reactant in humans, whose blood concentrations can rise 1000-fold in response to infection or inflammatory stimuli (Ji et al., 2023; Pathak and Agrawal, 2019; Pepys and Hirschfield, 2003). It is composed of five identical subunits and acts as a soluble PRR that recognizes phosphocholine (PC) ligands exposed on the surface of pathogens or damaged host cells (Bottazzi et al., 2010, Du Clos, 2013). Surface-bound pentameric CRP (pCRP) undergoes conformational changes resulting in the generation of monomeric CRP (mCRP) with greatly enhanced bioactivities (Badimon et al., 2018; Ji et al., 2023; McFadyen et al., 2020; Rajab et al., 2020; Wu et al., 2015). We have previously demonstrated that pCRP binds selectively to naïve CD4 + T cells and modulates their differentiation to Th1/Th2 effectors induced by TCR engagement (Zhang et al., 2015). The present study further shows that mCRP binds both naïve and memory CD4 + T cells, and tunes the conformational equilibrium of TCR, leading to the induction of engagement-independent, spontaneous TCR signaling and productive effector responses. These results thus identify a novel mode of bystander activation of CD4 + T cells, which depends on allosteric TCR signaling but not cognate antigens.