Table 4.

Summary of studies focusing on the effect of immunosuppressive agents on human Tfr.

Reference	Conditions	Sample	Definition	Major findings
Wallin EF et al, OBM Transplant. (2019)	Alemutuzumab induction for 19 SPK and 23 KTR vs 18 basiliximab treated KTR	Blood	CD4+ CXCR5+ FOXP3+ CD127lo	Tfr and Tfr : Tfh significantly lower in alemtuzumab treated patient up to 24 months post-transplant Trend toward lower Tfr in those developing de novo DSA
Wallin EF et al, Front Immunol. (2018) (99)	16 live donor KTR 1 week pre-treated with tacrolimus vs 45 deceased donor SPK or KTR	Blood and lymph node	CD4+ CXCR5+ FOXP3+ CD127lo	Decreased bTfh and lymph node Tfh. Trend towards fewer Tfr Co-culture of memory B cells and Tfh with tacrolimus showed lower plasmablast differentiation and antibody production
Chen W et al, Scientific reports (2017) (86)	30 controls	Blood	CD4+ CXCR5+ FOXP3+ CD127− ICOS+	In vitro tacrolimus increased Tfh1, decreased Tfh2 and Tfh17, no change in Tfr In vitro rapamycin reduced ratio of Tfr, no effect on Tfh1, Tfh2, and Tfh17 cells
	88 KTR with CAD incl.40 with biopsy proven ABMR			Overexpression of CTLA4 increased Tfr proportion and associated with less B cell proliferation
Niu Q et al, Expert Rev Clin Immunol. 2019 (100)	KTR on Tac, MMF and steroids	Blood	CD3+ CD4+ CXCR5+ FOXP3+	Lower numbers of bTfr associated with anti-HLA antibodies and worse renal function
Niu Q et al, Front Immunol. (2020) (61)	211 KTR 5-7 years after Tx, inc 24% with background of rejection 30 controls	Blood	CD3+ CD4+ CXCR5+ FOXP3+	Lower bTfr, no difference in bTfh, thus decreased bTfr : Tfh in KTR vs HC Previous rejection had reduced Tfh and Tfr – Tfr : Tfh same No association between anti-HLA antibodies or DSA and bTfr to Tfh Alemutuzumab and MP treated patients had significantly lower bTfr and bTfh

SPK, simultaneous pancreas kidney transplant; KTR, kidney transplant recipients; Tfr, T-follicular regulatory cell; bTfr, blood Tfr; CAD, chronic allograft dysfunction; ABMR, antibody-mediated rejection; Tx, transplantation; HLA, human leucocyte antigen; DSA, donor-specific antibodies; MP, methylprednisolone; Tac, tacrolimus; MMF, mycophenolate mofetil; HC, healthy controls.