Histology, T-Cell Lymphocyte


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Ryan Sauls


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Updated:
12/15/2018 3:51:29 PM

Introduction

T cells are a diverse and important group of lymphocytes that mature and undergo a positive and negative selection processes in the thymus, hence, the name T cells. These cells play a vital role in both components of active immunity (cell-mediated and to some extent humoral immunity). There are several types of T cells. The most common and well-known are the CD4+ T cells (helper T cells) and CD8+ T Cells (cytotoxic T cells, or killer T cells). T cells cannot recognize soluble, free antigens. T cells can only recognize protein based, receptor-bound antigens. This is achieved by use of the MHC (also known as HLA) 1 and 2 receptors, which along with the TCRs (T-cell receptors) bind the antigen in question and form a complex that allows the T cell to recognize the antigen. CD4+ T cells recognize MHC 2 bound antigens, while CD8+ T cells recognize MHC 1 bound antigens. Both CD4+ T cells and CD8+ T cells have the TCR (and the co-receptor CD3), but (as evidenced by their name) their other co-receptors vary. CD4+ T cells have CD4, whereas CD8+ T cells have CD8 as an added co-receptor. T cells are identified via flow cytometry for their CD markers as opposed to EM or light microscopy.

Issues of Concern

T-cell dysfunction is notable in several types of immunodeficiencies and autoimmune diseases, both acquired and genetic. Notably, T cells are the main targets of HIV and HTLV. T cells are also implicated in several types of neoplasms, such as T-cell acute lymphocytic leukemia (T-ALL) and adult T-cell lymphoma (ATL). T cells are often implicated in transplant rejection, and their surface receptors are pharmacologic targets for anti-rejection drugs. See clinical significance for further explanation.

Structure

All T lymphocytes have the TCR (T-cell receptor) and the pan-T-cell co-receptor CD3. It recognizes the antigen-loaded MHC molecules on other cells. Whether it can recognize MHC 1 or MHC 2 depends on its co-receptor (rather CD4 or CD8) as previously discussed. The TCR itself is a transmembrane receptor made up of various alpha and beta chains, each with variable regions. These variations develop to recognize different antigens and are selected for during the T-cell maturation process (involving positive and negative selection, within the thymus).[1][2] A small portion of T cells in the body have delta and gamma chains and recognize different antigen types than other T cells. These cells are a unique subpopulation called gamma-delta T cells and reside mostly in the mucosal epithelial layers of the body.[3] T cells also have various chemokine/co-receptors on their surfaces. The CCR5 and CXCR4 (found mostly on CD4+ T cells) chemokine receptors are of particular importance because they are the targets of HIV.[4][5]

The other structural markers of T cells depend on the T-cell type in question. CD4+ T cells have CD4, whereas CD8+ T cells have CD8 as an added co-receptor. T regulatory cells have CD4 and CD25 added as co-receptors for their TCRs. As mentioned above, T cells have numerous other biochemical receptors on their surface, and these largely depend on the T cell's function.[1][6]

Function

T-cell function is dependent on the type of T cell. The major T cells are CD8+ T cells, CD4+ T cells, and regulatory T cells (i.e., suppressor T cells). There are several other minor types of T cells are beyond this article. 

CD8+ T cells, also known as killer T cells (or cytotoxic T cells), are effector cells for cell-mediated immunity. Initially, CD8+ T cells are naive and must be activated to begin effector functions (i.e., immune functions). This activation occurs by interaction with pro-APCs (“professional” antigen-presenting cells), mainly dendritic cells in lymph nodules/follicles. This leads to an intracellular pathway that up-regulates more antigen-specific TCRs on the T cell and leads to effector functions. T cells can only recognize protein-based antigens. TCRs (T-cell receptor and their co-receptors, such as CD3 and CD8) found on these cells form a complex with the MHC 1 receptor and the antigen in question. Once an activated CD8+ migrates into circulation and finds its antigenic target (expressed on a virally infected cell or cell with intracellular bacteria, for example), it utilizes its killing function.[1] The killing function of CD8+ T cells is mediated by 1 of 2 mechanisms. The first mechanism involves the use of the Fas/Fas Ligand (FasL). Activated CD8+ T cells express FasL which binds to Fas (CD95), a receptor found on many cell types, leading to the activation of caspases and subsequent apoptosis of the target cell (often a cell infected with intracellular bacteria, such as Listeria species or a virally infected cell). The second method that activated CD8+ T cells can use for their killing function involves the release of granzymes and perforin (two compounds that bypass cell walls and active caspases). Activated CD8+ T cells also secrete IFN-? (a cytokine used in the activation of macrophages/other immune processes).[5][7]

CD4+ T cells, also known as helper T cells, are effector cells for cell-mediated immunity. Initially, CD4+ T cells are naïve and must be activated to begin effector functions (i.e., immune functions). This activation occurs by interaction with pro-APCs (“professional” antigen-presenting cells), mainly dendritic cells in lymph nodules/follicles. This leads to an intracellular pathway that up-regulates more antigen-specific TCRs on the T cell and leads to effector functions. T cells can only recognize protein-based antigens. TCRs (T cell receptor and their co-receptors, such as CD3 and CD4) found on these cells form a complex with the MHC 2 receptor and the antigen in question. The CD4+ cells are then activated and produce cytokines to initiate immune responses from other white blood cells/other immune cells of cell-mediated immunity. They also activate the T cell-dependent branch of humoral immunity, in which CD4+ T cells recognize protein antigens (which normally would elicit a weak or absent B cell response) and activate B cells to produce immunoglobulin in response to the antigen.[8][9]

There are three different subtypes of CD4+ T cells, each with a unique function: TH1 CD4+ T cells, TH2 CD4+ T cells, and TH17 CD4+ T cells. TH1 CD4+ cells are important in the activation of macrophages and fighting off intracellular infections. They secrete the cytokine IFN-gamma which activates macrophages, B cells (to produce IgG) and increased surface expression of the MHC 2 markers on macrophages/antigen-presenting cells. TNF-a is also secreted by these cells to activate dendritic cell migration. The activated macrophages then produced IL-12 which increases differentiation/production of TH1 T cells, further amplifying the immune response. TH1 T cells also play roles in several autoimmune reactions and disease, notably in delayed type hypersensitivity (DTH). TH2 CD4+ T cells are important in combating helminthic infections. These T cells produce IL-4, IL-5 and IL-13, which activate and expand mast cells and eosinophils to clear the parasitic infection.[10][11] Macrophages are also activated by these cells to begin clear of cellular debris and inflammation caused by large parasites. TH2 cells also appear to play a role in allergic diseases/allergies. TH17 CD4+ T cells are vital in mucosal immunity and are involved in combating extracellular bacteria, and fungi. TH17 cells produce IL17A, IL17F, and IL-22. These cytokines activate neutrophils and monocytes as well as increase inflammation. It is this pro-inflammatory function that appears to play a role in the development of autoimmune inflammatory disorders (such as inflammatory bowel disease and rheumatoid arthritis) when the response is pathogenic.[12][13][14]

The last major type of T cells is the T regulatory cell (alsop known as suppressor T cells). These cells modulate immune responses and inhibit autoimmune processes (such as autoreactive immune cells). T regulatory cells produce inhibitory IL-10 and IL-35 cytokines to control immune responses, as well as using CTLA-4 to inhibit B7 on antigen-presenting cells to decrease immune responses. Production of T regulatory cells is spurred by cytokine IL-2 (so much so that in autoimmune disease IL-2 is often absent) and TGF-beta. T regulatory cells express the TCR (CD3), CD4 (they likely share a common lineage with CD4+ Helper T cells), CTLA-4 and CD25. They also express the biomarker FOXP3 (a transcription marker important in their development and immune functions). There has been a recent interest in T regulatory cells as a method to promote wound healing after surgery and to battle cancers.[14][15]

Tissue Preparation

Normally, specimens are prepared with hematoxylin and eosin stain unless obtaining the sample for specific purposes. See Light Microscopy, Structure, Histochemistry, and EM microscopy sections for further details.

Histochemistry and Cytochemistry

The main histochemistry markers for T cells are their various surface receptors and signaling molecules. These markers have previously been discussed in the other sections. All T lymphocytes have the TCR and the pan-T cell co-receptor CD3. CD4+ T cells have CD4, whereas CD8+ T cells have CD8 as an added co-receptor. T regulatory cells have CD4 and CD25 added as co-receptors for their TCRs. Various chemokine receptors can also be used as T-cell markers, based on their respective functions. The CCR5 and CXCR4 (found mostly on CD4+ T cells) chemokine receptors are of particular importance because they are the targets of HIV.[2][4]

Microscopy Light

There is no way to differentiate between types of lymphocytes (B and T cells) under light microscopy; instead flow cytometry (identifying surface markers) is used. Lymphocytes under a light microscope are about the size of a red blood cell, around 7 micrometers, though some variation is expected. These cells have large, dark-staining nuclei (taking up most of the cell) due to having a lot of condensed chromatin. There is often only a small amount of pale, blue cytoplasm notable in these cells.[16]

Microscopy Electron

Electron microscopy of lymphocytes shows many prominent polyribosomes. Some note that it is possible to differentiate between T and B cells under EM, with T cells having an electron dense cytoplasm and euchromatin nucleus. Some studies have also noted that on surface examination T cells have a smoother surface than B cells. There is no way to differentiate the types of T cells.[16]

Clinical Significance

T-cell dysfunction is notable in several types of immunodeficiencies and autoimmune diseases, both acquired and genetic. Notably, T cells are the main targets of HIV and HTLV. T cells are also implicated in several types of neoplasms, such as T-cell acute lymphocytic leukemia (T-ALL) and adult T-cell lymphoma (ATL). T cells are often implicated in transplant rejection, and their surface receptors are pharmacologic targets for anti-rejection drugs.

T cells are specifically affected by several immunodeficiency disorders. Bare lymphocyte syndrome is an immunodeficiency in which T cells are selectively lost due to impaired MHC expression (due to genetic mutations in MHC production/expression). DiGeorge syndrome is another disorder that impacts T cells as the thymus never forms and thus T cells are never properly matured due to a deletion of the 22q11.21 through 22q11.23 chromosomal arms. Wiskott-Aldrich syndrome is an X-linked recessive disease in which the immune synapse is disordered, and T cells cannot react to foreign antigens. Various ZAP-70 and CD3 mutations impair TCR formation/function and cause T cell dysfunction too. Combined immunodeficiency’s (in which both B and T cells are affected) such as SCID and JAK3 deficiency also impair T cell function.[17][18]

Type IV hypersensitivity (delayed type hypersensitivity, also known as DTH) is CD4+ T cell-mediated and is implicated in contact dermatitis and granuloma formation and the basis for the tuberculin skin test. Systemic lupus erythematosus (SLE) is an autoimmune disorder in which autoreactive CD4+ T cells lead to the production of autoreactive antibodies (via B cell activation). A similar reaction occurs in rheumatoid arthritis (RA), in which autoreactive CD4+ TH17 and TH1 cells release autoreactive cytokines causing joint inflammation. IPEX is an autoimmune disorder in which FOPX3 mutations cause a loss of function in T regulatory cells and uninhibited T-cell activation, leading to widespread inflammation.[18][19]

HIV targets CD4+ T cells by binding to the CCR5 and CXCR4 chemokine receptors to infect them. Some note that in individuals with mutations to these receptors there is some immunity to HIV, due to HIV using them as its portal of cell entry. Human T-cell lymphotropic virus (HTLV) also specifically targets CD4+ T cells, using them to replicate. HTLV appears to use the adhesion molecules (used to migrate throughout the body by T cells) on cells surface to gain entry and replicate. HTLV infection eventually leads to the development of Adult T-cell leukemia/lymphoma (ATL). ATL is caused by HTLV activating NF-kappaB, which leads unregulated T-cell replication and expansion. T-cell acute lymphocytic leukemia (T-ALL) is also a T-cell centric neoplasm, caused by an activating mutation in NOTCH1. T cells are also heavily implicated in extra nodal T-cell lymphoma, various types of Hodgkin lymphomas and ALK + lymphomas. The type of T-cell response and which subtype responds to a pathogen is very important to fight off infections caused by Mycobacterium and Leishmania species, among others.[4][20][21][22]

T cells are often implicated in transplant rejection and their surface receptors are pharmacologic targets for many anti-rejection drugs. There has been a recent interest in T regulatory cells as a method to promote wound healing after surgery and to battle cancers. There is research to use all forms of T cells to combat a variety of diseases/enhance immune responses.[19]


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A patient presents with mild abdominal pain, unintended weight loss of 5 lbs over one week, and mild nausea and vomiting. A thorough patient history reveals consumption of under-cooked pork about two weeks ago. A Taenia solium infection is suspected and later confirmed. Which CD4+ (helper) T cell subtype response is most expected in this patient?



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A patient presents with worsening autoimmunity and is diagnosed with IPEX, involving FOXP3. What type of T cell is most likely impaired in this patient?



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Histology, T-Cell Lymphocyte - References

References

Lyu F,Ozawa T,Hamana H,Kobayashi E,Muraguchi A,Kishi H, A novel and simple method to produce large amounts of recombinant soluble peptide/major histocompatibility complex monomers for analysis of antigen-specific human T cell receptors. New biotechnology. 2018 Nov 19     [PubMed]
Bentzen AK,Such L,Jensen KK,Marquard AM,Jessen LE,Miller NJ,Church CD,Lyngaa R,Koelle DM,Becker JC,Linnemann C,Schumacher TNM,Marcatili P,Nghiem P,Nielsen M,Hadrup SR, T cell receptor fingerprinting enables in-depth characterization of the interactions governing recognition of peptide-MHC complexes. Nature biotechnology. 2018 Nov 19     [PubMed]
Melandri D,Zlatareva I,Chaleil RAG,Dart RJ,Chancellor A,Nussbaumer O,Polyakova O,Roberts NA,Wesch D,Kabelitz D,Irving PM,John S,Mansour S,Bates PA,Vantourout P,Hayday AC, The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness. Nature immunology. 2018 Dec     [PubMed]
Boyer Z,Palmer S, Targeting Immune Checkpoint Molecules to Eliminate Latent HIV. Frontiers in immunology. 2018     [PubMed]
Nakiboneka R,Mugaba S,Auma BO,Kintu C,Lindan C,Nanteza MB,Kaleebu P,Serwanga J, Interferon gamma (IFN-γ) negative CD4 and CD8 T-cells can produce immune mediators in response to viral antigens. Vaccine. 2018 Nov 17     [PubMed]
Wang Q,Ji X,Shao H,Ji Z,Zhu H,Shao X, [The decreased number of regulatory T cells in peripheral blood is accompanied by decreased autophagy in pediatric immune thrombocytopenia]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology. 2018 Sep     [PubMed]
Wu B,Lyu FL, [Progress of CD8 T cell-mediated immune response to Toxoplasma gondii infection]. Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology     [PubMed]
Shen H,Wu N,Nanayakkara G,Fu H,Yang Q,Yang WY,Li A,Sun Y,Drummer Iv C,Johnson C,Shao Y,Wang L,Xu K,Hu W,Chan M,Tam V,Choi ET,Wang H,Yang X, Co-signaling receptors regulate T-cell plasticity and immune tolerance. Frontiers in bioscience (Landmark edition). 2019 Nov 1     [PubMed]
Bourne N,Perry CL,Banasik BN,Miller AL,White M,Pyles RB,Schäfer H,Milligan GN, Increased frequency of virus shedding by herpes simplex virus type 2-infected guinea pigs in the absence of CD4 T lymphocytes. Journal of virology. 2018 Nov 21     [PubMed]
Williams JW,Ferreira CM,Blaine KM,Rayon C,Velázquez F,Tong J,Peter ME,Sperling AI, Non-apoptotic Fas (CD95) Signaling on T Cells Regulates the Resolution of Th2-Mediated Inflammation. Frontiers in immunology. 2018     [PubMed]
Hirata H,Yukawa T,Tanaka A,Miyao T,Fukuda T,Fukushima Y,Kurasawa K,Arima M, Th2 cell differentiation from naive CD4{sup} {/sup} T cells is enhanced by autocrine CC chemokines in atopic diseases. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2018 Nov 15     [PubMed]
Osborne LM,Brar A,Klein SL, The role of Th17 cells in the pathophysiology of pregnancy and perinatal mood and anxiety disorders. Brain, behavior, and immunity. 2018 Nov 19     [PubMed]
Kostrzewa-Nowak D,Nowak R, Analysis of selected T cell subsets in peripheral blood after exhaustive effort among elite soccer players. Biochemia medica. 2018 Oct 15     [PubMed]
Batista-Duharte A,Téllez-Martínez D,Roberto de Andrade C,Portuondo DL,Jellmayer JA,Polesi MC,Carlos IZ, Sporothrix brasiliensis induces a more severe disease associated with sustained Th17 and regulatory T cells responses than Sporothrix schenckii sensu stricto in mice. Fungal biology. 2018 Dec     [PubMed]
Jeon PH,Oh KI, IL2 is required for functional maturation of regulatory T cells. Animal cells and systems. 2017     [PubMed]
Polliack A,Siegal FP,Clarkson BD,Fu SM,Winchester RJ,Lampen N,Siegal M,De Harven E, A scanning electron microscopy and immunological study of 84 cases of lymphocytic leukaemia and related lymphoproliferative disorders. Scandinavian journal of haematology. 1975 Dec     [PubMed]
Kuo CY,Signer R,Saitta SC, Immune and Genetic Features of the Chromosome 22q11.2 Deletion (DiGeorge Syndrome). Current allergy and asthma reports. 2018 Oct 30     [PubMed]
Justiz Vaillant AA,Qurie A, Immunodeficiency null. 2018 Jan     [PubMed]
Charbonnier LM,Chatila TA, Phenotypic and Functional Characterization of Regulatory T Cell Populations null. 2018     [PubMed]
Lee JM,Han HJ,Choi WK,Yoo S,Baek S,Lee J, Immunomodulatory effects of intraoperative dexmedetomidine on T helper 1, T helper 2, T helper 17 and regulatory T cells cytokine levels and their balance: a prospective, randomised, double-blind, dose-response clinical study. BMC anesthesiology. 2018 Nov 8     [PubMed]
Georgieva ER, Non-Structural Proteins from Human T-cell Leukemia Virus Type 1 in Cellular Membranes-Mechanisms for Viral Survivability and Proliferation. International journal of molecular sciences. 2018 Nov 8     [PubMed]
Kim H,Kim IS,Chang CL,Kong SY,Lim YT,Kong SG,Cho EH,Lee EY,Shin HJ,Park HJ,Eom HS,Lee H, T-Cell Receptor Rearrangements Determined Using Fragment Analysis in Patients With T-Acute Lymphoblastic Leukemia. Annals of laboratory medicine. 2019 Mar     [PubMed]

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