eLetters for:

Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-1 infection

Barton F. Haynes, Laura P. Hale, Kent J. Weinhold, Dhavalkumar D. Patel, Hua-Xin Liao, Peter B. Bressler, Dawn M. Jones, James F. Demarest, Kristin Gebhard-Mitchell, Ashley T. Haase, John A. Bartlett

Published in Volume 103, Issue 4

J Clin Invest. 1999; 103(4):453 doi:10.1172/JCI5201

Abstract | Full text | PDF

A key question in understanding the status of the immune system in HIV-1 infection is whether the adult thymus contributes to reconstitution of peripheral T lymphocytes. We analyzed the thymus in adult patients who died of HIV-1 infection. In addition, we studied the clinical course of HIV-1 infection in three patients thymectomized for myasthenia gravis and determined the effect of antiretroviral therapy on CD4⁺ T cells. We found that five of seven patients had thymus tissue at autopsy and that all thymuses identified had inflammatory infiltrates surrounding lymphodepleted thymic epithelium. Two of seven patients also had areas of thymopoiesis; one of these patients had peripheral blood CD4⁺ T-cell levels of <50/mm³ for 51 months prior to death. Of three thymectomized patients, one rapidly progressed to AIDS, one progressed to AIDS over seven years (normal progressor), whereas the third remains asymptomatic at least seven years after seroconversion. Both latter patients had rises in peripheral blood CD4⁺ T cells after antiretroviral therapy. Most patients who died of complications of HIV-1 infection did not have functional thymus tissue, and when present, thymopoiesis did not prevent prolonged lymphopenia. Thymectomy before HIV-1 infection did not preclude either peripheral CD4⁺ T-cell rises or clinical responses after antiretroviral therapy.

Thymic output repertoire and peripheral T-cell receptor diversity

Kostense, Stefan | S_Kostense@clb.nl

CLB, Sanquin

From:
Stefan Kostense (1) and Frank Miedema (1,2)
(1) Dept. of Clinical Viro-Immunology, CLB, and Laboratory for Clinical and Experimental Immunology, Academic Medical Center
(2) Dept. of Human Retrovirology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Recently Haynes et al.(1) published a report on the role of the thymus in CD4 production during HIV-infection and treatment with HAART. Although we appreciate the major conclusions of their study, we wish to address the issue of T-cell receptor (TCR) diversity in relation to thymic function. The thymus is assumed to produce a diverse and complete repertoire. Hence absence of the thymus would not result in newly matured T cells comprising a diverse TCR repertoire, as Gorochov et al.(2) have observed in CD4 T-cells after introduction of highly active antiretroviral therapy (HAART). However, this can not be confirmed by complementarity determining region 3 (CDR3) spectratyping as they performed.
At first, normalisation of CDR3 size distributions can also result from loss/perishing of T cell clones which previously dominated the repertoire: decrease of a population with disturbed CDR3 size may allow detection of the less frequent, but polyclonal CDR3 sizes. Vice versa, clonal expansions can mask the polyclonal contribution of thymic output. Taken together, TCR diversity in PBMC does not invariably confirm or reflect the thymic function.
Furthermore, Gorochov et al. already showed that substantial differences exist between CD4 and CD8 TCR repertoires. The samples at week 3 and 13 studied by Haynes and colleagues, were derived from PBMC, thus including both CD4 and CD8 T cells. In a recent study, we reported that the CD4 subsets initially became more oligoclonal, coinciding with the early rise in peripheral T cells (week 8), and subsequently decrease in clonality approaching pre- treatment diversity (week45). We interpreted the early emergence of clonal expansions as redistribution of T cell clones from lymphoid tissue. This process is independent of a functional thymus. Therefore it should also occur in thymectomized patients. The reason that Haynes did not observe similar fluctuations may lie in the mixed T cell populations. Had we also used unpurified PBMC we probably would not have detected much alterations, since in the same patients, we observed an early decrease in clonality of the CD8 population (manuscript in preparation). For these patients the repertoire in PBMC largely depends on the CD4/CD8 ratio. Indeed Haynes showed only a few similar CDR3 patterns in CD4 and PBMC at week 47(1).
It is likely that thymectomy hampers the rebuilding of a complete T cell repertoire, however, the CDR3 spectratype data provided by Haynes et al. do not provide conclusive evidence in this.
1. Haynes, B.F., L.P. Hale, K.J. Weinhold, D.D. Patel, H.-X. Liao, P.B. Bressler, D.M. Jones, J.F. Demarest, K. Gebhard-Mitchell, A.T. Haase, and J.A. Bartlett. 1999. Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-1 infection. J.Clin.Invest. 103:453-460.
2. Gorochov, G., A.U. Neumann, A. Kereveur, C. Parizot, T. Li, C. Katlama, M. Karmochkine, G. Raguin, Autran B, and P. Debré. 1998. Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nature Med.4:215-221.
3. Kostense, S., F.M. Raaphorst, D.W. Notermans, J. Joling, B. Hooibrink, N.G. Pakker, S.A. Danner, J.M. Teale, and F. Miedema. 1998. Diversity of the TCRBV repertoire in HIV-1 infected patients reflects the biphasic CD4+ T-cell repopulation kinetics during HAART. AIDS 12:F235- F240