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. 2016 Oct 10;12(10):e1005903.
doi: 10.1371/journal.ppat.1005903. eCollection 2016 Oct.

Clinically Relevant Reactivation of Polyomavirus BK (BKPyV) in HLA-A02-Positive Renal Transplant Recipients Is Associated with Impaired Effector-Memory Differentiation of BKPyV-Specific CD8+ T Cells

Michiel C van Aalderen  1   2 , Ester B M Remmerswaal  1   2 , Kirstin M Heutinck  1   2 , Anja Ten Brinke  3 , Mariet C W Feltkamp  4 , Neelke C van der Weerd  2 , Karlijn A M I van der Pant  2 , Frederike J Bemelman  2 , René A W van Lier  3 , Ineke J M Ten Berge  1   2
Affiliations

Clinically Relevant Reactivation of Polyomavirus BK (BKPyV) in HLA-A02-Positive Renal Transplant Recipients Is Associated with Impaired Effector-Memory Differentiation of BKPyV-Specific CD8+ T Cells

Michiel C van Aalderen et al. PLoS Pathog. .

Abstract

Polyomavirus BK (BKPyV) frequently reactivates in immunosuppressed renal transplant recipients (RTRs) and may lead to graft loss due to BKPyV-induced interstitial nephritis (BKVN). Little is known on the differentiation of CD8+ T cells targeting BKPyV in RTRs. Here we investigated whether BKPyV-specific CD8+ T cell differentiation differs in RTRs with varying degrees of BKPyV reactivation and/or BKVN. Using combinatorial encoding with tetramers carrying BKPyV major capsid protein (VP1) and large T antigen protein (LTAG) epitopes, we investigated CD8+ T cell responses to BKPyV in longitudinally obtained PBMC samples from 46 HLA-A02-positive RTRs and 20 healthy adults. We were also able to isolate BKPyV-specific CD8+ T cells from five renal allografts, two of which were affected by BKVN. Before transplantation, BKPyV-specific CD8+ T cells targeting VP1 and LTAG epitopes appeared predominantly as central-memory and CD27+/CD28+ effector-memory (TEM), and naïve-like PD-1-expressing cells, respectively. After viral reactivation, BKPyV-specific CD8+ T cells assumed CD28- TEM and TEMRA states in patients who were able to control BKPyV, whereas differentiation lagged behind in patients with severe viral reactivation or BKVN. Furthermore, VP1-specific CD69+/CD103+ tissue-resident memory (TRM) cells accumulated in BKVN-affected allografts but lacked signs of effector differentiation. In contrast, granzyme B-expressing effector cells were detected in allografts not affected by BKVN. In conclusion, effector-memory differentiation of BKPyV-specific CD8+ T cells in patients with high viral load or BKVN is impaired. Further characterization of the specific mechanisms behind this altered cellular differentiation is necessary to develop therapies that can prevent the emergence of BKVN.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1
(A) anti-VP1 antibody levels in NR, Rlow, Rhigh and BKVN patients shortly before transplantation and one year after transplantation. (B) Viral load during follow-up of Rlow, Rhigh and BKVN patients (left panel) and viral load plotted against the peak viral load (right panel). (C) From left to right: Population sizes of VP1- (open symbols) and LTAG-specific (closed symbols) CD8+ T cells detected in healthy individuals, in all RTRs before transplantation, in NR patients before—and one year after transplantation and in the Rlow, Rhigh and BKVN during follow-up. (D) Expression frequency of Ki-67 by VP1- (open symbols) and LTAG-specific (closed symbols) CD8+ T cells in healthy individuals, in NR patients before—and one year after transplantation and in the Rlow, Rhigh and BKVN RTRs during follow-up.
Fig 2
Fig 2
(A) Scatter plots and pie charts showing the distribution of the seven largest CD45RA/CCR7/CD28/CD27-defined human CD8+ T cell populations, as described previously [21], amongst VP1- (first column) and LTAG-specific (second column) CD8+ T cell populations detected in healthy individuals (first row) and all RTRs (second row) before transplantation. (B) from left to right the expression of T-bet, Eomes, granzyme B, granzyme K (first row) and IL-7Rα (CD127), PD-1 and CD95 (second row) by VP1- (open symbols) and LTAG-specific (closed symbols) CD8+ T cells detected in healthy individuals and in all RTRs before transplantation.
Fig 3
Fig 3
(A) Pie charts depicting the distribution of the seven largest CD45RA/CCR7/CD28/CD27-defined human CD8+ T cell populations, as described previously [21], amongst VP1- (left panel) and LTAG-specific (right panel) CD8+ T cell populations detected in NR, Rlow, Rhigh and BKVN RTRs during follow-up. (B) Representative dot plot overlays showing the fluorescence intensities of CD45RA, CCR7, CD28 and CD27 with the total CD8+ T cell events shown in grey and LTAG-specific events in black from one Rlow patient (upper row) and one BKVN patient (lower row) during follow-up.
Fig 4
Fig 4
(A) Scatter plots showing the expression frequencies of T-bet (upper panel) and Eomes (lower panel) by VP1- (open symbols) and LTAG-specific (closed symbols) CD8+ T cell populations detected in NR patients before—and one year after transplantation, and in the Rlow, Rhigh and BKVN RTRs during follow-up. (B) Representative dot plot overlays showing the fluorescence intensities of T-bet and Eomes with the total CD8+ T cell events shown in grey and LTAG-specific events in black from one Rlow patient (upper row) and one BKVN patient (lower row) during follow-up.
Fig 5
Fig 5
(A) Scatter plots showing the expression frequencies of IL-7Rα by VP1- (open symbols) and LTAG-specific (closed symbols) CD8+ T cell populations detected in NR patients before—and one year after transplantation, and in the Rlow, Rhigh and BKVN RTRs during follow-up. (B) Representative dot plot overlays showing the fluorescence intensities of T-bet and IL-7Rα with the total CD8+ T cell events shown in grey and LTAG-specific events in black from one Rlow patient (upper row) and one BKVN patient (lower row) during follow-up.
Fig 6
Fig 6
(A) Scatter plots showing the expression frequencies of granzyme K (upper panel) and granzyme B (lower panel) by VP1- (open symbols) and LTAG-specific (closed symbols) CD8+ T cell populations detected in NR patients before—and one year after transplantation, and in the Rlow, Rhigh and BKVN RTRs during follow-up. (B) Representative dot plot overlays showing the fluorescence intensities of granzyme K and granzyme B with the total CD8+ T cell events shown in grey and LTAG-specific events in black from one Rlow patient (upper row) and one BKVN patient (lower row) during follow-up.
Fig 7
Fig 7. Scatter plots showing the production of CD107a (first row), IL-2 (second row), IFNγ (third row) and TNFα (last row) by VP1- (open symbols) and LTAG-specific (closed symbols) CD8+ T cell populations detected after stimulation in vitro in healthy individuals, NR patients before—and one year after transplantation, and in the Rlow, Rhigh and BKVN RTRs during follow-up.
Fig 8
Fig 8
(A) Line graphs showing the paired percentages of BKPyV VP1- and LTAG-specific CD8+ T cells amongst the total CD8+ T cell pool in the peripheral blood (PB) and in the kidney for 2 BKVN patients (first column) and three other RTRs (middle and right columns) (B) Dot plot overlays showing the fluorescence intensities of CD013 and CD69, and of (C) CD45RA and CD27, and (D) CD103 and granzyme B in the PB and in the kidney.
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