NK cells lyse T regulatory cells that expand in response to an intracellular pathogen.
We evaluated the capacity of NK cells to influence expansion of CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) in response to microbial Ags, using Mycobacterium tuberculosis as a model. We previously found that Tregs expand when CD4(+) cells and monocytes are exposed to M. tuberculosis. Addition of NK cells that were activated by monokines (IL-12, IL-15, and IL-18) or by exposure to M. tuberculosis-stimulated monocytes reduced Treg expansion in response to M. tuberculosis. NK cell inhibition of Treg expansion was not mediated through IFN-gamma. Activated NK cells lysed expanded, but not freshly isolated Tregs. Although monokines increased NK cell expression of the activating receptors NKp46, NKG2D, 2B4, CD16, and DNAM-1, only anti-NKG2D and anti-NKp46 inhibited NK cell lysis of expanded Tregs. Of five NKG2D ligands, only UL16-binding protein 1 (ULBP1) was up-regulated on M. tuberculosis-expanded Tregs, and anti-ULBP1 inhibited NK cell lysis of expanded Tregs. M. tuberculosis-stimulated monocytes activated NK cells to lyse expanded Tregs, and this was also inhibited by anti-NKG2D and anti-ULBP1, confirming the physiological relevance of this effect. Our study identifies a potential new role for NK cells in maintaining the delicate balance between the regulatory and effector arms of the immune response.
Roy
Sugata
S
Center for Pulmonary and Infectious Disease Control, Department of Microbiology and Immunology, University of Texas Health Center, 11937 U.S. Highway 271, Tyler, TX 75708, USA.
Barnes
Peter F
PF
Garg
Ankita
A
Wu
Shiping
S
Cosman
David
D
Vankayalapati
Ramakrishna
R
D015704:CD4 Antigens / Q000032:analysis; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D051858:Forkhead Transcription Factors / Q000032:analysis; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015846:Monokines / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000819:agonists; D055607:Receptors, Natural Killer Cell; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000382:microbiology*
D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D053645:Interleukin-2 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D008565:Membrane Proteins; D015846:Monokines; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C423231:ULBP1 protein, human; D007371:Interferon-gamma