TCRγδ+ and CD161+ Thymocytes Express HIV-1 in the SCID-hu Mouse, Potentially Contributing to Immune Dysfunction in HIV Infection

Abstract

The vast diversity of the T cell repertoire renders the adaptive immune response capable of recognizing a broad spectrum of potential antigenic peptides. However, certain T cell rearrangements are conserved for recognition of specific pathogens, as is the case for TCRγδ cells. In addition, an immunoregulatory class of T cells expressing the NK receptor protein 1A (CD161) responds to nonpeptide Ags presented on the MHC-like CD1d molecule. The effect of HIV-1 infection on these specialized T cells in the thymus was studied using the SCID-hu mouse model. We were able to identify CD161-expressing CD3+ cells but not the CD1d-restricted invariant Vα24/Vβ11/CD161+ NK T cells in the thymus. A subset of TCRγδ cells and CD161-expressing thymocytes express CD4, CXCR4, and CCR5 during development in the thymus and are susceptible to HIV-1 infection. TCRγδ thymocytes were productively infectable by both X4 and R5 virus, and thymic HIV-1 infection induced depletion of CD4+ TCRγδ cells. Similarly, CD4+CD161+ thymocytes were depleted by thymic HIV-1 infection, leading to enrichment of CD4−CD161+ thymocytes. Furthermore, compared with the general CD4-negative thymocyte population, CD4−CD161+ NK T thymocytes exhibited as much as a 27-fold lower frequency of virus-expressing cells. We conclude that HIV-1 infection and/or disruption of cells important in both innate and acquired immunity may contribute to the overall immune dysfunction seen in HIV-1 disease.

Limited correlation between human thymus and blood NKT cell content revealed by an ontogeny study of paired tissue samples

“…This is consistent with the study from Baev and colleagues [22], but contrasts with earlier suggestions that NKT cells may be absent from the postnatal thymus [20,21]. The difference in NKT cell frequency between thymus and blood from the same donor was surprisingly high.…”

“…1). In previous studies of NKT cells from human thymus, NKT cell staining was performed without the use of a separate dump channel [20][21][22]. Although this strategy effectively identifies NKT cells in the blood, the published thymus FACS profiles appear consistent with our own experiences in which the absence of exclusion gating allows low levels of background staining to encroach upon the NKT cell region.…”

“…No previous study has directly examined NKT cells from thymus and blood of the same donors, but previous reports showing very few DN and CD8 + NKT cells in cord blood and thymus (of different donors) led to speculation that these subsets arise in the periphery [21,22]. The possibilities raised in those studies were that the establishment of peripheral NKT cell subsets occurred by preferential expansion of CD4 -NKT cells [22], down-regulation of CD4 by CD4 + NKT cells (and presumably up-regulation of CD8 in some cases) [21], or thymus-independent production of CD4 -NKT cells [20].…”

“…The earliest study utilized fresh thymus tissue from infants, and the SCID-hu model, in which T cells develop within mice engrafted with human thymus tissue and progenitor lymphocytes [20]. NKT cells were not detected within fresh or grafted thymus, leading to the conclusion that peripheral NKT cells may develop independently of the thymus.…”

Development of innate CD4+α-chain variable gene segment 24 (Vα24) natural killer T cells in the early human fetal thymus is regulated by IL-7

“…Data presented in a recent study (39) indicated that V␣24 NK T cells were not present in the postnatal human thymus. This finding was interpreted to suggest that these cells develop in a thymusindependent manner (39).…”