CD16+ monocytes control T-cell subset development in immune thrombocytopenia

Abstract

IntroductionClassic differentiation of naive CD4 ϩ T cells into different T helper (Th) subsets, including Th1, Th2, and Th17, occurs in lymphoid tissues after contact with antigen-presenting cells that produce polarizing cytokines. These Th subsets in turn orchestrate diverse immune responses also mediated by production of distinct cytokines. Because aberrant Th1 or Th17 activities have the potential to trigger chronic inflammatory and autoimmune diseases, 1,2 effector Th responses in healthy persons are under tight regulation mediated in part by CD4 ϩ regulatory T cells (Tregs) that are thymic-derived or naive T cell-inducible. 3 Understanding how Th1/Th17/Treg differentiation and expansion are controlled is likely to provide an explanation of how inflammation may be sustained in pathologic environments.More recently, human monocytes were shown to trigger and polarize Th responses 4,5 as well as to both stimulate and suppress T-cell responses during infection and in autoimmune diseases. 5,6 Monocytes, which are generally regarded as precursors of tissue macrophages and dendritic cells, 7 can be phenotypically divided based on surface expression of CD14 (lipopolysaccharide receptor) and CD16 (low affinity Fc␥ receptor III) expression into subsets, each with distinct functional activities. The major monocyte subpopulation characterized by high CD14 but no CD16 expression (CD14 hi CD16 Ϫ ), also referred to as classic monocytes, have higher phagocytic activity. 8 The minor CD16 ϩ cells produce higher TNF after stimulation and expand under infectious or inflammatory conditions. 9,10 With regards to the control of Th differentiation and reactivation, the specific role of the monocyte subsets has not been fully characterized.Immune thrombocytopenia (ITP) is an autoimmune bleeding disease resulting from decreased platelet production as well as accelerated platelet destruction mediated in part by autoantibody-based destruction mechanisms. 11 ITP patients harbor activated platelet-autoreactive T cells with increasing cytokine imbalance toward IL-2 and IFN-␥ 12-14 as well as altered Treg numbers and function. [15][16][17][18][19][20] A shift toward stimulatory monocytes with enhanced Fc␥R-mediated phagocytic capacity further supports a generalized immune dysregulation in ITP. 21 More recently, studies reported increased Th17 cells or IL-17 cytokine in ITP patients, 22-24 implicating a possible role for Th17 cells in ITP immunopathology, although 2 reports did not detect any difference. 25,26 Among the treatment options available to ITP patients, the recently licensed thrombopoietic agents, by increasing platelet production, have yielded overall durable responses in patients with persistent, chronic, and/or refractory ITP while on treatment. 27 Interestingly, improved Treg function in ITP patients was associated with increased platelet counts after the use of these agents, 28 despite apparent lack of immunomodulatory activity associated with such agents. Similarly, improved Treg compartment was reported in ITP patients w...

Pathological Role of Regulatory T Cells in the Initiation and Maintenance of Eczema Herpeticum Lesions

“…Considering the dual role of Tregs in EH, therapeutic interventions on the expanded Tregs seem complicated and warrant additional studies. With regard to how pMOs affect the Treg compartment, a few recent studies (24,34) revealed their inhibitory effect on Treg expansion, contrary to our current data. In the current study, we demonstrated that pMOs detected in the acute stage of EH were characterized by the potent ability to expand Tregs, probably through their increased production of IL-10 and their decreased production of IL-1b, TNF-a, and IL-6, which were quite different from those detected in healthy controls, ADEH 2 patients, and ADEH patients at the resolution stage.…”

“…Recently, Zhong et al (24) reported that pMOs can control peripheral Treg development in immune thrombocytopenia. Because we demonstrated in this study that pMOs in ADEH have the ability to produce more IL-10 and less proinflammatory cytokines than their normal counterparts, we investigated whether pMOs derived from AD patients at the onset of EH could induce iTreg expansion, unlike their counterparts in thrombocytopenia.…”

Pivotal Role for CD16+ Monocytes in Immune Surveillance of the Central Nervous System

“…In summary, alterations in the composition of the mobile CSF monocyte pool may reflect a shift of CD16 + monocytes from the periphery to sites of inflammation. Such a compartmentalization, which is typical for MS, may account for the difference in monocyte subgroup distributions in other autoimmune diseases (7)(8)(9)(10)(11)(12)(13)(14)(15). CD16 + non-classical so-called patrolling monocytes exert important functions in the peripheral immune compartment.…”

“…Increased frequencies of circulating CD16 + monocytes have been reported in various autoimmune diseases such as sarcoidosis (7,8), rheumatoid arthritis (9-11), inflammatory bowel diseases (12), Sjögren syndrome (13), asthma (14), and immune thrombocytopenia (15).…”

Platelet analysis in laboratory hematology

“…That this non-antibody-mediated mechanism exists is quite easy to see in the bone marrow cytology, since the increased megakaryopoiesis is reduced despite a clinical diagnosis of ITP, with PIFT, MAIPA and SASPA being negative, the reticulated platelets not elevated, and withoutapoptotic megakaryocytes being present. The role of T-cells in ITP has been limited to the regulatory T-cells so far [24][25][26][27][28] and one publication has actually placed the antigen-presenting monocytes ahead of the T-cells [29]. Conversely, in a study with a drug that induces LGL, the positive correlation was shown [30].…”