Figure 1.

Potential mechanisms of immune cells and inflammatory storm in PD-1 induced colitis. PD-1 expressed by T cells can bind to PD-L1 ligands activated by tumor cells, thereby inhibiting T cell activation. PD-1 inhibitors such as pembrolizumab, nivolumab and sintilimab block these processes to enhance the T cell anti-tumor response. With high expression of T-bet, the balance of CD4⁺ T cells is tilted toward Th1 cells, which is dominant compared with Th2 cells. Moreover, tissue-resident memory T cells (Trms) rapidly differentiate into CTLs and Th1 cells, and secrete the pro-inflammatory factors like TNF-α, IFN-γ and GZMB. ILC3 was enriched in intestinal mucosal tissues. As irAEs occur and grow in severity, the absolute number of B cells decreases. However, CXCR5+ T follicular helper cells (Tfhs) accumulate in the germinal centers and plasma expression of the B lymphocyte chemokine ligand CXCL13 increases, ultimately allowing for B cell-mediated overproduction of autoantibodies and immunoglobulins. In PD-1-induced colitis, there is not only a change in the immune cell profile, but also an onslaught of inflammatory storms. NLRP3 inflammasome expression and induction of IL-1β release are found to be higher in myeloid cells. IL-6 induces an increase in CXCL8, which encodes a neutrophil chemotactic molecule, giving rise to the number of neutrophils. IFN-γ plays an essential role in the interaction between T cells and myeloid cells, as it stimulates high expression of CXCL9, CXCL10, and CXCL16 in myeloid cells, allowing T cell populations expressing CXCR3 and CXCR6 chemokine receptors to be rapidly recruited to inflamed tissues and secrete IFN-γ, which eventually formed a closed loop of the IFN signaling pathway.