Effective Lysis of HIV-1-Infected Primary CD4+ T Cells by a Cytotoxic T-Lymphocyte Clone Directed Against a Novel A2-Restricted Reverse-Transcriptase Epitope

CD4 T cells activated in vitro by anti-CD3/28–coated beads are resistant to infection by CC chemokine receptor 5 (CCR5)-dependent HIV-1 isolates. In vivo, antigen-presenting cells (APCs) activate CD4 T cells in part by signaling through the T cell receptor and CD28, yet cells stimulated in this manner are susceptible to HIV-1 infection. We show that cytotoxic T lymphocyte antigen 4 (CTLA-4) engagement counteracts the CD28 antiviral effects, and that the ratio of CTLA-4 to CD28 engagement determines the susceptibility of HIV-1 infection. Furthermore, unopposed CTLA-4 signaling provided by CD28 blockade promotes vigorous HIV-1 replication, despite minimal T cell proliferation. Finally, CTLA-4 antibodies decrease the susceptibility of antigen-activated CD4 T cells to HIV, suggesting a potential approach to prevent or limit viral spread in HIV-1–infected individuals.

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Differential HIV Epitope Processing in Monocytes and CD4 T Cells Affects Cytotoxic T Lymphocyte Recognition

The Journal of Infectious Diseases ◽

10.1086/599837 ◽

2009 ◽

Vol 200 (2) ◽

pp. 236-243 ◽

Cited By ~ 22

Author(s):

Estibaliz Lazaro ◽

Sasha Blue Godfrey ◽

Pamela Stamegna ◽

Tobi Ogbechie ◽

Christopher Kerrigan ◽

...

Keyword(s):

T Cells ◽

T Lymphocyte ◽

Cd4 T Cells ◽

Cytotoxic T Lymphocyte

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Induction of Cytotoxic T Lymphocyte Antigen 4 (Ctla-4) Restricts Clonal Expansion of Helper T Cells

Journal of Experimental Medicine ◽

10.1084/jem.194.7.893 ◽

2001 ◽

Vol 194 (7) ◽

pp. 893-902 ◽

Cited By ~ 70

Author(s):

Alden M. Doyle ◽

Alan C. Mullen ◽

Alejandro V. Villarino ◽

Anne S. Hutchins ◽

Frances A. High ◽

...

Keyword(s):

T Cells ◽

T Cell Activation ◽

T Lymphocyte ◽

Cd4 T Cells ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Clonal Expansion ◽

Negative Regulator ◽

Lymphocyte Antigen ◽

Cell Divisions

Cytotoxic T lymphocyte antigen (CTLA)-4 plays an essential role in immunologic homeostasis. How this negative regulator of T cell activation executes its functions has remained controversial. We now provide evidence that CTLA-4 mediates a cell-intrinsic counterbalance to restrict the clonal expansion of proliferating CD4+ T cells. The regulation of CTLA-4 expression and function ensures that, after ∼3 cell divisions of expansion, most progeny will succumb to either proliferative arrest or death over the ensuing three cell divisions. The quantitative precision of the counterbalance hinges on the graded, time-independent induction of CTLA-4 expression during the first three cell divisions. In contrast to the limits imposed on unpolarized cells, T helper type 1 (Th1) and Th2 effector progeny may be rescued from proliferative arrest by interleukin (IL)-12 and IL-4 signaling, respectively, allowing appropriately stimulated progeny to proceed to the stage of tissue homing. These results suggest that the cell-autonomous regulation of CTLA-4 induction may be a central checkpoint of clonal expansion of CD4+ T cells, allowing temporally and spatially restricted growth of progeny to be dictated by the nature of the threat posed to the host.

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