γδ T cell-mediated immune responses in disease and therapy

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Transcript of γδ T cell-mediated immune responses in disease and therapy

  • REVIEW ARTICLEpublished: 10 November 2014

    doi: 10.3389/fimmu.2014.00571

    T cell-mediated immune responses in disease andtherapyT. Sree Latha1, Madhava C. Reddy 2, Prasad V. R. Durbaka3, Aparna Rachamallu4,5, Reddanna Pallu4,5 andDakshayani Lomada1*1 Department of Genetics and Genomics, Yogi Vemana University, Kadapa, India2 Department of Biotechnology and Bioinformatics, Yogi Vemana University, Kadapa, India3 Department of Microbiology, Yogi Vemana University, Kadapa, India4 Department of Animal Biology, University of Hyderabad, Hyderabad, India5 National Institute of Animal Biotechnology (NIAB), Hyderabad, India

    Edited by:Julie Dechanet-Merville, CentreNational de la Recherche Scientifique(CNRS), France

    Reviewed by:David Escors, University CollegeLondon, UKDavid Vermijlen, Universit Libre deBruxelles (ULB), Belgium

    *Correspondence:Dakshayani Lomada, Department ofGenetics and Genomics, Room # 124,Sir CV Raman Science Complex, YogiVemana University, Kadapa, AP516003, Indiae-mail: dlomada@yahoo.com,dlomada@yogivemanauniversity.ac.in

    The role of T cells in immunotherapy has gained specific importance in the recent yearsbecause of their prominent function involving directly or indirectly in the rehabilitation ofthe diseases. T cells represent a minor population ofT cells that express a distinctT cellreceptor (TCR) composed of chains instead of chains. Unlike T cells, T cellsdisplay a restricted TCR repertoire and recognize mostly unknown non-peptide antigens. T cells act as a link between innate and adaptive immunity, because they lack pre-cise major histocompatibility complex (MHC) restriction and seize the ability to recognizeligands that are generated during affliction. Skin epidermal T cells recognize antigenexpressed by damaged or stressed keratinocytes and play an indispensable role in tis-sue homeostasis and repair through secretion of distinct growth factors. T cell basedimmunotherapy strategies possess great prominence in the treatment because of theproperty of their MHC-independent cytotoxicity, copious amount of cytokine release, anda immediate response in infections. Understanding the role of T cells in pathogenicinfections, wound healing, autoimmune diseases, and cancer might provide knowledgefor the successful treatment of these diseases using T cell based immunotherapy.Enhancing the human V9V2 T cells functions by administration of aminobisphospho-nates like zoledronate, pamidronate, and bromohydrin pyrophosphate along with cytokinesand monoclonal antibodies shows a hopeful approach for treatment of tumors and infec-tions. The current review summarizes the role of T cells in various human diseases andimmunotherapeutic approaches using T cells.

    Keywords: T cells, pathogenic infections, cancer, autoimmunity, wound healing, immunotherapy

    INTRODUCTIONT cells are the principal lymphocytes that play a vital role in cell-mediated immune responses. Majority of the T cells are T cellswith and chains and a minor population of T cells doexist that play a pivotal role in the host defense system (1). Tcells are located in peripheral blood (PB), intestine, skin, spleen,and lymph nodes where they were found to act as interface forthe cross talk between innate and cell-mediated immune cells (2).The functional development of T cells is initiated much ear-lier than the development of T cells in embryogenesis, where T cell Receptor (TCR) gene rearrangements were detected inthe fetal thymus by day 14 of embryogenesis (E14). The earli-est murine T cell wave expresses V3V1 and gives rise toskin dendritic epidermal T cells (DETC). Later, vaginal and gutintra-epithelial T lymphocytes (IEL) and immune organ Tcells were developed (3). V3V1 DETCs are exclusively generatedin the fetal thymus, migrate to epidermal epithelia, expand locallyand are maintained throughout the life of an individual (4). Tcells express TCR molecule on their cell surface, but there are onlya few variable genes available to construct V/V TCR proteins. In

    addition, the usage of the V/V genes is not random but appearsto be dictated by the localization of T cells (5). Hence T cellsare well engaged in newborns to contribute to immune-protectionand immune-regulation (6, 7).

    TCR recognize non-peptide antigens like glycerolipids andother small molecules, polypeptides that are soluble or mem-brane anchored, and cross linked to major histocompatibil-ity complex (MHC) molecules or MHC-like molecules in anantigen-independent manner (8). Human V9V2 (also known asV2V2) T cells can be activated by metabolites from isoprenoidsynthetic pathway. These include (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), exogenous prenyl pyrophosphatefrom bacteria and parasitic protozoa and isopentenyl pyrophos-phate (IPP), and endogenous prenyl pyrophosphate deriving frommevalonate pathway that operates in human. Aminobisphospho-nates may activate V9V2 T cells by inhibiting the key enzymefarnesyl pyrophosphate synthase of mevalonate pathway in cer-tain tumors leads to upregulating the endogenous pool of IPP(9). Vavassori et al. identified butyrophilin BTN3A1 molecule,which is involved in the presentation of phosphorylated antigens to

    www.frontiersin.org November 2014 | Volume 5 | Article 571 | 1


  • Latha et al. T cells in disease and therapy

    V9V2 T cells (10). Recently, Sandstrom et al. demonstrated thatintracellular B30.2 domain of butyrophilin 3A1 (BTN3 A1) pro-tein binds phosphoantigens (pAg) to mediate activation of humanV9V2 T cells. This intracellular B30.2 domain of BTN3A1directly binds pAg through a positively charged surface pocketand charge reversal of pocket residues abrogates binding andactivation of V9V2 T cells (11). Furthermore, Uldrich et al.reported that CD1d presents lipid-based antigens to human V1+

    T cells (12). T cells use both the TCR and also addi-tional activating receptors like natural killer (NK) cell activatingreceptor (NKG2D), toll like receptor (TLR), and NOTCH sig-naling to respond to stress induced ligands and infection (13).Activated T cells promote the anti-infection capabilities of res-ident macrophages, NK cells, and also enhance the maturationof dendritic cells (DCs). Besides that, they secrete cytokines andchemokines to recruit pro-inflammatory neutrophils to acceleratethe elimination of pathogens and the repair of damaged tissues.Neutrophils in turn suppress the T cells activation to reducethe inflammation when the infection has been resolved (14). Inaddition, T cells in the skin produce keratinocyte growth fac-tor (KGF), important cytokine for wound repair, and epithelialcell regeneration. It has been demonstrated that the human T cells activation and expansion can be controlled by forkheadbox P3 (FOXP3) expressing regulatory T cells (Tregs), programeddeath-1 (PD-1), and cytotoxic T lymphocyte antigen (CTLA)-4both in vivo and in vitro (15).

    T cells bridge innate and adaptive immunity and play a pro-tective role in immune-surveillance. Effector T cells produceinterferon (IFN)-, tumor necrosis factor (TNF)-,which enhancecell-mediated immune response and interleukin (IL)-17 that playsa vital role in early neutrophil mediated response. In addition,cytotoxic components such as perforin, granzymes secreted bythese cells ultimately cause direct or indirect effect of cytotoxicityagainst infected cells (16). They provide a wide range of defensemechanisms against microorganisms such as viruses,bacteria,pro-tozoa, and diseases like cancer and also in healing of wounds andburns. In addition, T cells also play a role in autoimmune dis-eases such as rheumatoid arthritis (RA) and systemic lupus erythe-matosus (SLE) through their antigen-presenting capacity, releaseof pro-inflammatory cytokines, immunomodulatory properties,interaction with Tregs, and promotion of antibody production(17). Pantelyushin et al. reported that apart from retinoid-relatedorphan receptor gamma-t (RORt+) innate lymphocytes, Tcells also produce cytokines like IL-17A, IL-17F, and IL-22 that areessential and enough for psoriatic plaque formation in a diseasemodel that closely resembles human psoriatic plaque formation(18). Current review exclusively focuses on the role T cellsin specific pathogenic infections, anti-tumor activity, healing ofwounds and burns, autoimmune diseases, and few insights ontheir immunotherapy.

    PATHOGENIC INFECTIONSTUBERCULOSISTuberculosis caused by Mycobacterium tuberculosis (Mtb) is con-sidered to be one of the serious infectious disease worldwidecausing 1.7 million deaths every year. Around 30% of the worldspopulation is affected by M. tuberculosis and approximately 100

    million people died due to tuberculosis (TB) over the last century(19). Hence, there is an urgent need to find out the host factorsthat delineate the individuals susceptible to TB. pAg such IPP andHMBPP are the key ligands that activateV9V2 T cells. HMBPP isnearly 1000-fold more effective than IPP for the in vitro activationof V9V2 T cells (20). Mtb produces HMBPP, which is recog-nized by V9V2 TCR and drives the activation of V9V2 T cells(21). Effector V9V2 T cells are shown to pa