How immunosuppressive therapy affects T cells from kidney transplanted patients of different age: the role of latent cytomegalovirus infection

Abstract

The average age of patients receiving renal transplantation is increasing as programmes have been established which support the donation of organs from elderly donors to older recipients. Little is known about the effect of immunosuppressive therapy on the immune system of older patients. In this study, T cell function and the composition of the T cell repertoire were analysed in immunosuppressed renal transplant recipients of different age and cytomegalovirus (CMV) status in comparison to age- and CMV-matched controls. Independent of age and CMV status, the production of interleukin (IL)-2 and interferon (IFN)-γ by T cells was decreased in the patient groups and autologous serum from patients was capable of inhibiting the proliferation of CD3⁺ T cells. CXCR5 expression on T cells was increased in patients versus controls reflecting reduced endogenous IL-2 signalling under immunosuppressive therapy. In CMV-seronegative patients kidney transplantation and immunosuppressive therapy did not induce changes in the CD8⁺ T cell pool, but there was a moderate increase in CD4⁺CD28⁻ effector T cells when compared to age-matched controls. In contrast, latent CMV infection triggered a shift from early to late differentiated CD4⁺ and CD8⁺ T cells in patients and controls. This shift was most pronounced in elderly transplant patients under immunosuppressive therapy. In conclusion, our results demonstrate that immunosuppressive therapy following kidney transplantation is effective in patients older than 65 years. Latent CMV infection, however, accelerates age-related changes in the T cell repertoire in elderly people under immunosuppressive therapy. These patients should therefore be monitored with special care.

Keywords: T cells; ageing; immunosuppressive therapy.

Figure 1

Interleukin (IL)-2 and interferon (IFN)-γ production of CD3⁺ T cell from kidney transplanted immunosuppressed patients of different age compared to age-matched healthy controls. IL-2 and IFN-γ production was analysed by intracellular staining and fluorescence activated cell sorter (FACS) analysis. Horizontal lines represent mean values. Cytomegalovirus (CMV)-positive individuals are marked by black symbols. *P < 0·05; **P < 0·01; ***P < 0·001; kidney transplanted patients (KTx) versus healthy controls (HC).

Figure 2

Proliferation of T cells from kidney transplanted immunosuppressed patients. (a) Proliferation index of T cells from healthy subjects (HC) and kidney transplanted patients (KTx) stimulated with anti-CD3 (3 ng/ml) and cultured in medium containing 10 % fetal calf serum (FCS) for 5 days. Proliferation was assessed by carboxyfluorescein succinimidyl ester (CFSE) staining and is expressed as proliferation index. Bars represent mean ± standard error of the mean [healthy controls (HC): n = 34, KTx: n = 46]. (b) Representative histogram of CFSE-labelled T cells from a kidney transplanted patient after 5 days of culture with anti-CD3 (3 ng/ml) in the presence of 10 % FCS, 5% autologous serum or 10% autologous serum, respectively. (c) Effect of incubation with FCS or autologous serum on the proliferation of T cells from KTx immunosuppressed patients of different age and cytomegalovirus (CMV) status (squares indicated CMV-seropositive, circles indicate CMV-seronegative individuals).

Figure 3

CXCR5 expression in CD3⁺ T cells of healthy controls (HC) and kidney transplanted immunosuppressed patients (KTx). (a) A representative staining experiment showing the expression of CXCR5 in CD3⁺ T cells from one KTx patient and one HC. (b) Percentages of CXCR5⁺ CD3⁺ cells in the different age groups. CMV-positive individuals are marked by black symbols. The horizontal lines represent mean values. **P < 0·01; ***P < 0·001; HC versus KTx.