Increased circulating Tfh to Tfr ratio in chronic renal allograft dysfunction: a pilot study

Abstract

Background: T follicular helper (Tfh) cells play a control role in contribution of B cell differentiation and antibody production. T follicular regulatory (Tfr) cells inhibit Tfh-B cell interaction.

Methods: To identify whether circulating Tfh (cTfh) and Tfr (cTfr) cells contribute to chronic renal allograft dysfunction (CAD), 67 kidney transplant recipients (34 recipients with CAD, 33 recipients with stable function) were enrolled. The frequency of cTfh and cTfr cells, the level of serum CXCL13 were measured.

Results: The frequency of cTfr cells in CAD group was significantly lower than that in stable group (0.31% vs 0.68%, P = 0.002). The cTfh to cTfr ratio in CAD group was significantly higher than that in stable group (55.4 vs 25.3, P = 0.013). Serum CXCL13 in CAD group was significantly higher than stable group (30.4 vs 21.9 ng/ml, P = 0.025). After linear regression analysis, the cTfh to cTfr ratio was an independent risk factor for estimated glomerular filtration rate (eGFR) in recipients (standardized coefficient = - 0.420, P = 0.012). After logistic regression analysis, the cTfh to cTfr ratio was an independent risk factor for CAD (OR = 1.043, 95%CI = 1.004-1.085, P = 0.031).

Conclusion: The imbalance between cTfh and cTfr cells contribute to the development of CAD.

Keywords: CXCL13; Chronic renal allograft dysfunction; T follicular helper cells; T follicular regulatory cells; cTfh to cTfr ratio.

Fig. 1

Dot plots of cTfh, cTfr cells and their isotypes between CAD group and stable group. a Representative of dot plots and percentage (%) of cTfh (CXCR5⁺Foxp3⁻/CD4⁺) cells and their isotypes between CAD group and stable group; b Representative of dot plots and percentage (%) of cTfr (CXCR5⁺Foxp3⁺/CD4⁺) cells and their isotypes between CAD group and stable group

Fig. 2

The frequency of cTfh and cTfr cells and the level of associated factors between CAD group and stable group. Squares refer to chronic allograft dysfunction (CAD) group, cycles refer to stable renal function group; a cTfh: CXCR5⁺Foxp3⁻ on CD4⁺ cells; b cTfr: CXCR5⁺Foxp3⁺ on CD4⁺ cells; c cTfh to cTfr ratio; d Tregs: CD25⁺Foxp3⁺ on CD4⁺ cells; e CXCR5⁺PD-1⁺ on CD4⁺ cells; f PD-1⁺ on CXCR5⁺CD4⁺ cells; g CXCR5⁺ICOS⁺ on CD4⁺ cells; h ICOS⁺ on CXCR5⁺CD4⁺; i CXCR5⁺STAT3⁺ on CD4⁺ cells; j CXCR5⁺STAT5⁺ on CD4⁺ cells; k STAT3⁺ on CXCR5⁺CD4⁺ cells; l STAT5⁺ on CXCR5⁺CD4⁺ cells; m CXCR5⁺STAT4⁺ on CD4⁺ cells; n STAT4⁺ on CXCR5⁺CD4⁺ cells; o CXCR5⁺IL-21⁺ on CD4⁺ cells; p IL-21⁺ on CXCR5⁺CD4⁺ cells; q The serum level of CXCL13; r The serum level of TGF-β

Fig. 3

The frequency of cTfr cells, cTfh to cTfr ratio and the expression of ICOS, STAT3, STAT5 between BPR group and stable group. Squares refer to biopsy-proven rejection (BPR) group, cycles refer to stable renal function group; a cTfr: CXCR5⁺Foxp3⁺ on CD4⁺ cells; b cTfh to cTfr ratio; c CXCR5⁺ICOS⁺ on CD4⁺ cells; d ICOS⁺ on CXCR5⁺CD4⁺; e CXCR5⁺STAT3⁺ on CD4⁺ cells; f STAT3⁺ on CXCR5⁺CD4⁺ cells; g CXCR5⁺STAT5⁺ on CD4⁺ cells; h STAT5⁺ on CXCR5⁺CD4⁺ cells

Fig. 4

The frequency of cTfr cells, cTfh to cTfr ratio and the expression of ICOS between DSA positive group and stable group. Squares refer to donor specific antibody (DSA) group, cycles refer to stable renal function group; a cTfr: CXCR5⁺Foxp3⁺ on CD4⁺ cells; b cTfh to cTfr ratio; c CXCR5⁺ICOS⁺ on CD4⁺ cells; d ICOS⁺ on CXCR5⁺CD4⁺