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The first signal required for B-cell activation is delivered through its antigen receptor (top panel). For thymus-dependent antigens, the second signal is delivered by a helper T cell that recognizes degraded fragments of the antigen as peptides bound to MHC class II molecules on the B-cell surface (center panel); the interaction between CD40 ligand (CD40L) on the T cell and CD40 on the B cell contributes an essential part of this second signal. For thymus-independent antigens, the second signal can be delivered by the antigen itself (lower panel), or by non-thymus-derived accessory cells (not shown).

Mechanisms and signaling pathways mediating the development of systemic CRS and CAR T-cell cardiotoxicity. At lymph node tumor sites, autologous CART cells encounter and recognize tumor antigens on CD19 positive cancer cells, leading activated T-cell release of cytolytic granules (i.e., granzymes and perforins) that promote tumor cell lysis and death. At the tumor site, macrophages can also interact with activated T cells via CD40L to CD40 binding. This binding promotes the release of INFy, TNFɑ, GM-CSF, and activation of macrophages. Activated macrophages release proinflammatory cytokines (IL-1, IL-6, TNFɑ, INFy, iNOS), which mediate increases monocyte recruitment from blood and into myocardial tissue. Unchecked overstimulation of immune cells also precipitates supra-physiologic increases of cytokines and development of CRS. Elevated blood cytokines levels increase membrane permeability and vascular leak causing fever, hypotension, hypoxia, multi-organ toxicity and cardiac dysfunction including tachycardia, myocarditis, de novo arrythmias, HF, and sudden cardiac death. There is evidence to suggest that direct activation of IL-1, IL-6, and TNFɑ signaling in cardiomyocytes may also promote perturb Ca²⁺ homeostasis leading to impaired cardiac contractility and cardiac remodeling. Activation of TNFR1 and TNFR2 may precipitate caspase-mediated apoptosis, increased NO, increased mitoROS, and reduced SR Ca²⁺ uptake. IL-1 activation of cardiomyocyte IL-1R1signaling reduces ß-adrenergic signaling, LTCC I_Ca²⁺, and SR Ca²⁺ cycling. Both cardiomyocyte IL-1R1 and TNFR2 activation can also promote NFkB-mediated increases transcription of inflammation genes. Finally, increased cytokines can also elicit a decrease in connexin protein (CX43/CX40) expression, which contributes to the development of arrhythmias. T-cell infiltration of the myocardium can also promote direct antigen cross-reactivity with cardiac self-antigens. (Created with Biorender.com). Abbreviations: AF atrial fibrillation; AKT protein kinase B; AP-1 activator protein 1; ASK1 apoptosis signal–regulating kinase 1; CAR chimeric antigen receptor; CD19 cluster of differentiation 19 receptor; CD40 cluster of differentiation 40; CD40L cluster of differentiation 40 ligand; c–Jun Jun proto–oncogene; CRS cytokine release syndrome; CX43 connexin 43; CX40 connexin 40; DAMPS damage–associated molecular patterns; ERK extracellular signal–regulated kinase 1/2; ECM extracellular matrix; INFy interferon gamma; gp130 glycoprotein 130; IL–1 interleukin–1; IL–1R1 interleukin 1 receptor type 1; IL–6 interleukin 6; iNOS inducible nitric oxide synthase; JAK janus tyrosine kinase; JNK c–jun N–terminal kinase; LTCC L–type calcium channel; MAPK mitogen–activated protein kinase; MEK mitogen–activated protein kinase; Mito-ROS mitochondrial reactive oxygen species; MHCI/II major histocompatibility complex 1/2; NO nitric oxide; NF–kB nuclear factor kappa B; PRR pattern recognition receptors; PI3K phosphoinositide 3–kinase; p38 p38 mitogen–activated protein kinase; Raf rapidly accelerated fibrosarcoma protein; RAS rat sarcoma virus protein; ROS radical oxygen species; sIL–6R soluble IL–6 receptor; SR sarcoplasmic reticulum; STAT3 signal transducer and activator of transcription 3; TNFɑ tumor necrosis factor alpha; TNFR1/2 tumor necrosis factor receptor 1/2; TRADD tumor necrosis factor receptor type 1–associated death domain; TRAF2 tumor necrosis factor receptor associated factor 2