Table 2.

Checkpoints of Tregs in sepsis

Checkpoint	Ligand	Signaling	Class	Function to Tregs
PD1	PD-L1	Notch pathway	Co-inhibitory receptor	Increase Foxp3 expression Induce Treg expansion Enhance Treg's immunosuppressive ability.
CTLA-4	CD80/86		Co-inhibitory receptor	Competitively bind to and reduces the expression of CD80/CD86 costimulatory molecules on APCs, thereby depriving Tconv cells of the necessary costimulatory signal.
BTLA	HVEM (CD270)		Co-inhibitory receptor	Enhance Treg's suppressive function
TIM3	Ceacam-1 HMGB-1	STAT-3 phosphorylation IL10, EBI3, GZMB, PRF1, IL1Rα, and CCR6 expression	Co-inhibitory receptor	Regulate the balance between regulatory and effector T cells.
TIGIT	CD155 CD226 Nectin-2		Co-inhibitory receptor	Leads to FOXP3 demethylation
OX40	OX40L	NFκB, PI3K, ERK, and AKT signaling	Costimulatory molecule	Maintain Treg's suppressive ability: suppress effector T cell proliferation or IFN-γ production.
Nrp1	SEMA3A SEMA4A TGF-β & TGF-βRI/II/III	Smad signaling neuropilin-1-semaphorin-4a axis		Support the stability and functional maintenance of Tregs by regulating semaphorin-4a Reduce apoptosis of Tregs and lower the methylation levels of Foxp3-TSDR Involve the production of IL-10 and TGF-β in Treg cells
CD39 and CD73	ATP			CD39 mediates the elimination of ATP-associated effects in Treg cells CD73 mediates immune suppression by adenosine production