Human T cell reconstitution in DiGeorge syndrome and HIV-1 infection

Abstract

The thymus is essential for proper development and maintenance of a broad T cell repertoire capable of recognizing a wide-range of foreign antigens. Recent advances in multicolor flow cytometry, non-invasive imaging techniques, and molecular assessments of thymic function have enabled a more comprehensive characterization of human thymic output in clinical settings than in the past. These techniques have been particularly valuable in monitoring human T cells after therapeutic thymic grafting for complete DiGeorge syndrome and during HIV-1 infection and AIDS. By defining the degree and mechanisms of T cell reconstitution in these settings, clinical investigators and primary caregivers have been able to better diagnose, treat and care for individuals with congenital or acquired immune deficiencies associated with loss of thymic function.

Figures

Fig. 1

Generation of Signal Joint (sj) TRECs During TCRA Rearrangement. Simplified representation of the TCRD locus flanked by portions of the TCRA locus. Rearrangement of the TCRA gene forms a single TREC containing an unique sj sequence. (Adapted and used with permission from reference [1]).

Fig. 2

Schematic outline of Human TCRβ spectratyping (immunoscope) to determine T cell repertoire diversity.

Fig. 3

An allograft used for thymus transplantation. A) H&E 40x on day of harvest, B) H&E 40x on day of transplantation 21 days later, C) cytokeratin (AE1/AE3) 40x on day of harvest, D) cytokeratin 40x on day of transplantation.

Fig. 4

Biopsy of thymus allograft at 2.5 months after transplantation. A) H&E 10x, B) cytokeratin (AE1/AE3) 40x, C) CD3 40x, D) Ki-67 40x. A collection of lymphocytes is seen in the muscle. At higher power, the graft shows lacy cytokeratin with CD3+ T cells many of which are positive for Ki-67, a cortical thymocyte marker.

Fig. 5

Kaplan Meier Survival curve of infants with complete DiGeorge anomaly. Survival of 32 infants out of 44 transplanted with thymus tissue is shown.

Fig. 6

T cell development after thymus transplantation in a typical patient. A. T cell subsets, B. Naïve T cells, C. PHA response. In A, the 10th percentiles for CD3, CD4, and CD8 numbers for children aged 2–6 years are shown as horizontal lines [110]. In B the 10th percentiles for naïve CD4 and naïve CD8 T cells for children aged 2–6 years are indicated by the lines [110]. In C the geometric mean plus and minus one standard deviation of the adult control responses are shown.

Fig. 7

In situ hybridization for HIV-1 RNA in end-stage thymus tissue. Present in the black box are HIV-1 infected cells in the perivascular space (P) and the thymic epithelium (E). Keratin positive (brown) empty epithelium indicates a loss of thymopoiesis (40x). Histology photographs generously provided by Dr. Laura P. Hale (Duke University Department of Pathology).

Fig. 8

Thymus function in biopsy tissue from HIV-1 infected donors with (A) or without ARV (B). Shown are chest CT scans, CD4/CD8 FACS plots of isolated thymocytes and H&E stained tissue sections of the intact thymus biopsy. Thymic perivascular space (P) and epithelium (E) are referenced (10x). Histology photographs generously provided by Dr. Laura P. Hale (Duke University Department of Pathology) [70].