Biology of chronic graft-vs-host disease: Immune mechanisms and progress in biomarker discovery

Table 2 Immune cell types and their function in chronic graft-vs-host disease

Cell type	Subtypes	Key cytokines or markers	Brief summary of disease involvement
CD4+ T cells	Th1	IFN-γ, TNF-α	Pro-inflammatory. Important in acute GVHD, but role in cGVHD unclear
	Th2	IL-4, IL-13	Stimulate antibody production. Role in clinical cGVHD poorly defined
	Th17	IL-17; also IL-21, IL-22, TNF-α	Pro-inflammatory. IL-17 levels correlate with disease severity; IL-17 induces scleroderma of skin and lung
	Tregs	TGF-β, required for Treg proliferation and (differentiation)	Produced mostly in thymus. Suppress autoreactive T cells. Lower levels of Tregs present in cGVHD patients, associated with thymic damage and loss of self-tolerance in cGVHD
	T follicular helper cells1	Express CCR5, PD-1 and ICOS	Promote abnormal B cell maturation into long-lived active plasma cells, and IgG secretion
CD8+ T cells		CXCL9, CXCL10	Mediate graft-vs-tumor effect of transplant. Serum CXCL9 levels elevated in cGVHD patients
B cells (total)		Increased BAFF/B-cell ratio, elevated serum BAFF levels	Decreased in active cGVHD. Remaining B cells are resistant to apoptosis
Naïve and transitional B cells		CD19	Decreased in active cGVHD
Memory B cells (total)		CD19, CD27	Decreased in active cGVHD. Cells essential for a normal immune response to bacterial pathogens or opportunistic infections
Regulatory B cells		IL-10	Decreased in active cGVHD. Function to maintain tolerance and help prevent autoimmune disease
Plasma cells		CD27, CD38	Increased in active cGVHD. Cells secrete immunoglobulins including IgGs and are resistant to apoptosis

¹Mainly classified into Th2 and Th17 subtypes[44]. cGVHD: Chronic graft-vs-host disease; BAFF: B-cell activating factor; CD3: Cluster of Differentiation molecule 13, 19, 27 and 38; CCR5: Chemokine (C-C Motif) receptor 5; CXCL: Chemokine (C-X-C motif) ligand; ICOS: Inducible T-Cell Co-Stimulator; IFN-γ: interferon gamma; IL: Interleukin; PD-1: Programmed cell death 1; Th: T helper cell; TGF-β: Transforming growth factor beta; TNF-α: Tumor necrosis factor alpha.