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Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets.

ABSTRACT: Interleukin-7 (IL-7) is a homeostatic cytokine for resting T cells with increasing serum and tissue levels during T cell depletion. In preclinical studies, IL-7 therapy exerts marked stimulating effects on T cell immune reconstitution in mice and primates. First-in-human clinical studies of recombinant human IL-7 (rhIL-7) provided the opportunity to investigate the effects of IL-7 therapy on lymphocytes in vivo. rhIL-7 induced in vivo T cell cycling, bcl-2 up-regulation, and a sustained increase in peripheral blood CD4(+) and CD8(+) T cells. This T cell expansion caused a significant broadening of circulating T cell receptor (TCR) repertoire diversity independent of the subjects' age as naive T cells, including recent thymic emigrants (RTEs), expanded preferentially, whereas the proportions of regulatory T (T reg) cells and senescent CD8(+) effectors diminished. The resulting composition of the circulating T cell pool more closely resembled that seen earlier in life. This profile, distinctive among cytokines under clinical development, suggests that rhIL-7 therapy could enhance and broaden immune responses, particularly in individuals with limited naive T cells and diminished TCR repertoire diversity, as occurs after physiological (age), pathological (human immunodeficiency virus), or iatrogenic (chemotherapy) lymphocyte depletion.

SUBMITTER: Sportes C

PROVIDER: S-EPMC2442646 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets.

Sportès Claude C Hakim Frances T FT Memon Sarfraz A SA Zhang Hua H Chua Kevin S KS Brown Margaret R MR Fleisher Thomas A TA Krumlauf Michael C MC Babb Rebecca R RR Chow Catherine K CK Fry Terry J TJ Engels Julie J Buffet Renaud R Morre Michel M Amato Robert J RJ Venzon David J DJ Korngold Robert R Pecora Andrew A Gress Ronald E RE Mackall Crystal L CL

The Journal of experimental medicine 20080623 7

Interleukin-7 (IL-7) is a homeostatic cytokine for resting T cells with increasing serum and tissue levels during T cell depletion. In preclinical studies, IL-7 therapy exerts marked stimulating effects on T cell immune reconstitution in mice and primates. First-in-human clinical studies of recombinant human IL-7 (rhIL-7) provided the opportunity to investigate the effects of IL-7 therapy on lymphocytes in vivo. rhIL-7 induced in vivo T cell cycling, bcl-2 up-regulation, and a sustained increase ...[more]

PMID: 18573906

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Project description:A broad T cell receptor (TCR-) repertoire is required for an effective immune response. TCR-repertoire diversity declines with age. End-stage renal disease (ESRD) patients have a prematurely aged T cell system which is associated with defective T cell-mediated immunity. Recently, we showed that ESRD may significantly skew the TCR V?-repertoire. Here, we assessed the impact of ESRD on the TCR V?-repertoire within different T cell subsets using a multiparameter flow-cytometry-based assay, controlling for effects of aging and CMV latency. Percentages of 24 different TCR V?-families were tested in circulating naive and memory T cell subsets of 10 ESRD patients and 10 age- and CMV-serostatus-matched healthy individuals (HI). The Gini-index, a parameter used in economics to describe the distribution of income, was calculated to determine the extent of skewing at the subset level taking into account frequencies of all 24 TCR V?-families. In addition, using HI as reference population, the differential impact of ESRD was assessed on clonal expansion at the level of an individual TCR V?-family. CD8+, but not CD4+, T cell differentiation was associated with higher Gini-TCR indices. Gini-TCR indices were already significantly higher for different CD8+ memory T cell subsets of younger ESRD patients compared to their age-matched HI. ESRD induced expansions of not one TCR V?-family in particular and expansions were predominantly observed within the CD8+ T cell compartment. All ESRD patients had expanded TCR V?-families within total CD8+ T cells and the median (IQ range) number of expanded TCR V?-families/patient amounted to 2 (1-4). Interestingly, ESRD also induced clonal expansions of TCR V?-families within naive CD8+ T cells as 8 out of 10 patients had expanded TCR V?-families. The median (IQ range) number of expanded families/patient amounted to 1 (1-1) within naive CD8+ T cells. In conclusion, loss of renal function skews the TCR V?-repertoire already in younger patients by inducing expansions of different TCR V?-families within the various T cell subsets, primarily affecting the CD8+ T cell compartment. This skewed TCR V?-repertoire may be associated with a less broad and diverse T cell-mediated immunity.

Dataset Information

Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets.

Publications

Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets.

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