Costimulatory Pathways: Physiology and Potential Therapeutic Manipulation in Systemic Lupus Erythematosus

Table 1

Summary of the signalling mechanisms and physiological actions of major co-stimulatory molecules in systemic lupus erythematosus.

Costimulation receptor (ref.)	Costimulation ligand	Family	Cells expressing	Signaling molecules involved	Action
*CD80; *CD86; [79, 80]	CD28	IgSF	CD80/86: APCs including monocytes, M𝜙, and DC; CD28: mainly naive CD4+ & CD8+ T cells during their initial phase of activation	CD28: phosphorylation by Lck and FYN, and ITK which recruits PI3K and Grb2 PI3K converts PI to PIP3 and activates Akt and subsequently NF-𝜅B; Grb2 binds to SOS1, phosphorylates VAV1 which in turn activates Rac1 and JNK	CD80/86 are constitutively expressed on APCs and B cells CD80/86 are upregulated by inflammation and stimulation of T cells, and they provide costimulatory signals to CD28 and CTLA-4 Stimulation of CD28 prolongs and augments IL-2 production from T cells and prevents the development of peripheral immune tolerance
	CTLA-4	IgSF	T cells during late stage of activation	CTLA-4: phosphorylation by Lck, FYN, and RLK, binds to PI3K, SHP-2, and PP2A. PLC𝛾, and AKT, and hence proinflammatory effector signals are suppressed	Attenuates further costimulation between communicating immunocytes, dampens proinflammatory signals, and produces anergy. CTLA-4 expression induces CD28 endocytosis on activated T cells
B7RP1; [81]	ICOS	CD28-B7 family	ICOS: activated T cells; B71RP1: APCs and B cells	ICOS: phosphorylation of ERK, JNK, and p38	ICOS stimulation induces further activation and clonal expansion of T cells, germinal centre formation, and T-cell- dependent antibody formation
CD137; [82, 83]	CD137L	TNFSF	CD137: activated T cells, NK-T cells; CD137L: APCs, B cells	CD137L: Src tyrosine kinase which activates MEK1/2, P38 MAPK, subsequently, and NF-𝜅B (human). Association with TNFR1 which mediates reverse signalling	CD137 enhances proliferation of, and memory as well as cytolytic functions of T cells. It Inhibits CD4+ response and ameliorates autoimmunity due to IFN𝛾 production by CD8+ T cells; CD137L induces myelopoiesis, DC maturation, B-cell stimulation, and T-cell proliferation
CD27; [84]	**CD70	TNFSF	CD70: activated T and B cells and Mϕ; CD27: resting T and NK cells, some in B cells	CD27 binds to TRAF 2/5 after trimerization and activates NF-𝜅Band the c-Jun pathway; CD70 activates PI3K, Erk1/2, and MAPK	CD27 stimulation suppresses Th17 effector function and enhances B-cell activation and Ig production. CD70 signalling may regulate cell cycle of B cells and cytotoxicity of T cells
^†OX40; [85, 86]	^‡OX40L	TNFSF	OX40: T cells; OX40L: APCs, glomerular endothelial cells	OX40L binds to OX40, recruits TRAF 2, 3, 5, and induces phosphorylation of IκBα, and subsequently NF-𝜅B, PI-3K, and protein; kinase B	OX40 signalling increases the longevity of T cells and subsequent cytokine production and expansion of memory T-cell population. OX40L signalling enhances B-cell proliferation and differentiation; OX40L inhibits the generation of IL-10 producing CD4+ Tregs from naive and memory T cells
CD40; [87]	^€CD40L	TNFSF	CD40: B cells; CD40L: T cells	CD40: TRAF 1/2, 3/5, 5, 6, and induces NF-𝜅B while TRAF 2, 2/6, and 6 induces p38, Akt and JNK Jak 3 and induces STAT5 phosphorylation	Provides a strong activation signal to B cells for their differentiation, proliferation, and hence germinal centre development, and Ig response to T-dependent antigens. CD40 also upregulates CD80/86 expression and provides further stimulation signals to T cells.

Abbreviations: ref: references; CD: cluster of differentiation; IgSF: immunoglobulin superfamily; APCs: antigen-presenting cells; Mϕ: macrophages; DC: dendritic cells; TNFSF: tumour necrosis factor superfamily; Lck: lymphocyte-specific protein tyrosine kinase; FYN: protooncogene tyrosine-protein kinase Fyn; ITK: IL2-inducible T-cell kinase; PI3K: Phosphoinositide 3-kinase; Grb2: Growth factor receptor-bound protein 2; PI: phosphatidylinositol; PIP3: phosphatidylinositol (3,4,5)-trisphosphate; Akt: PKB is a serine/threonine protein kinase; NF-𝜅B: nuclear factor-kappa-light-chain-enhancer of activated B cells; Sos: son of sevenless homolog 1; Vav1: protooncogene vav; Rac1: Ras-related C3 botulinum toxin substrate 1; JNK: c-Jun N-terminal kinase; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; IL: interleukin; RLK: receptor-like kinase; SHP-2: Src homology region 2 domain-containing phosphatase-2; PP2A: Protein phosphatase 2A; PLC𝛾: Phospholipase C𝛾; B7RP1: B7 related protein 1; ICOS: inducible co-stimulator; ERK: extracellular-signal-regulated kinases; NK-T: natural killer T cells; MEK1/2: mitogen-activated protein kinase kinase 1/2; MAPK: mitogen-activated protein kinase; TNFR1: TNF receptor 1; IFN𝛾: interferon gamma; TRAF: TNF-receptor-associated factors; IkB: inhibitor of κB; Jac3: Janus kinase 3; and STAT5: signal transducers and activators of transcription 5; Ig: immunoglobulin.
∗CD80 = B7-1, CD86 = B7-2; ∗∗CD70 = CD27L; ^†OX40 = CD134; ‡OX40L = CD134L; and ^€CD40L = CD154.