T cell and B Cell Signaling Pathways

TSLP TSLPR IL-7Ra CCL19 CCL21 CCR7 CCL1 CCL16 CCR8 4-1BB OX40 CD200R CD40L CD28 CD80 CD86 TNFR TNFα TNFR2 TNFβ CXCR3 CXCL10 CXCL9 CTLA-4 CD80 CD86 CCR6 CCL20 CCR5 CCL3 CCL4 CCL5 CD3 LIGHT HVEM LTβR CCR4 CCL17 CCL22 CXCR5 CXCL13 gp130 OSM OSMRβ DR3 TL1A PD-L2 PD-L1 PD-1 CD47 SIRPα MAdCAM-1 Integrin α4β7 BAFF BAFF-R CXCR5 CXCL13 TSLPR IL-7Ra TSLP CD19 CD20 CCR7 CCL19 CCL21 CXCR4 CXCL12 BCMA BAFF APRIL TAC1 APRIL BAFF TLR9 CpG DNA/dsDNA CCR6 CCL20 CTLA-4 CD80 CD86 CD40 CD200 OX40L 4-1BBL

Background

Aberrant T-cell activation is a central driver of many autoimmune diseases. T-cell activation requires two key inputs: a primary signal delivered through T-cell receptor (TCR) recognition of peptide–MHC complexes, and a secondary costimulatory signal, such as the interaction between CD28 and CD80/CD86. This second signal is essential for maintaining immune homeostasis and preventing excessive immune responses. Dysregulation of these pathways—particularly excessive costimulation or insufficient inhibitory signaling through immune checkpoints such as CTLA-4 or PD-1—can lead to uncontrolled T-cell activation and subsequent immune-mediated tissue damage.

B cells, in addition to being the primary source of antibody production, also function as potent antigen-presenting cells and secrete cytokines that modulate immune responses. Loss of B-cell tolerance is a defining feature of autoimmune pathology. B-cell activation is orchestrated by four major receptor classes: the B-cell receptor (BCR), cytokine receptors, receptors mediating cognate T–B interactions (including immune checkpoint molecules), and innate immune receptors such as Toll-like receptors (TLRs). Among these, TLR signaling plays a particularly important role by promoting three key pathogenic mechanisms in B-cell–driven autoimmunity: autoantibody generation, antigen presentation to T cells, and cytokine secretion.

Pathologic T–B cell crosstalk: T- and B-cell dysregulation in autoimmune disease is highly interconnected. Autoreactive T cells provide costimulatory cues—such as CD40L engagement of CD40—that drive B-cell activation and autoantibody production. Conversely, B cells present self-antigens to T cells, further amplifying T-cell activation. Consequently, therapeutic strategies that target critical nodes within T- and B-cell signaling networks—by suppressing aberrant activation, reducing pathogenic lymphocyte subsets, or interrupting inflammatory signaling—have become foundational approaches for treating autoimmune disorders.