Lecture 26: gd T and NKT Cells - Immunology PDF

Chapter 11: gd T and NKT cells  gd T cells: overview In both humans and mice, the majority of T cells in the body are CD4+ or CD8+ ab T cells. In contrast, gd T cells express TCRs composed of TCRg and TCRd chains plus the CD3 complex. They carry either homodimeric CD8a...

Chapter 11: gd T and NKT cells  gd T cells: overview In both humans and mice, the majority of T cells in the body are CD4+ or CD8+ ab T cells. In contrast, gd T cells express TCRs composed of TCRg and TCRd chains plus the CD3 complex. They carry either homodimeric CD8aa coreceptors or no coreceptor at all & are thus referred to as double negative peripheral T cells. gd-T cells are minor population of T cells in mice & humans, but a major population in ruminants (cows, sheep) & pigs.  gd T cells: overview In contrast to ab TCRs which recognize only pMHC complexes, gd TCRs interact with ligands in a way similar to ligand recognition by pattern recognition receptors (PRRs). Thus, gd T cells can respond to Ags that are derived from a broad range of pathogens or abnormal/stressed host cells. gd T cells do not require involvement of MHC or processing & presentation of peptide Ags by APCs. Intact proteins or peptides from pathogens or stressed host cells, & non-protein Ags such as lipids & phosphorylated nucleotides can serve as TCRgd ligands. TCRgd ligands may be soluble or bound to a cell surface.  gd T cells: overview Some stress molecules that can be recognized by gd T cells are not recognized by myeloid cells such as neutrophils & macrophages, so gd T cells fill critical gaps in host defense. Once activated, gd T cells respond by proliferating and differentiating into gd Th and gd CTL effectors like ab T cells. However, they do so more rapidly, in smaller numbers, & often in the absence of conventional costimulation. Thus, some immunologist picture gd T cells as being in a ‘resting but preactivated’ state ideal for innate defense. The release of cytokines by gd T cells can precede the activation of ab T cell by several days.  gd T cells: Anatomical distribution The anatomical distribution of gd T cells is strikingly different from that of ab T cells. Only very low numbers of gd T cells are found in secondary lymphoid tissues and thymus of mice and humans. Instead, gd T cells are interspersed among the epithelial cells of the skin (SALT) & in the mucosae of various body tract (MALT). This allows them to be among the first defenders to confront invading pathogens or injurious substances.  gd T cells: Anatomical distribution Unlike ab T cells, gd T cells resident in a particular tissue express a dominant or ‘canonical’ TCR containing specific V gene segments. For example, in humans, Vg1Vd2 TCRs are prevalent on intestinal gd T cells, whereas Vg9Vd2 TCRs occur on gd T cells in the skin and peripheral blood.  gd T cells: Ag recognition and activation Unlike ab TCR, the TCRs of many gd T cells can bind directly to low molecular weight non-peptide antigens, without the need for presentation by another molecule or cells. However, some non-peptide Ags are also presented by non- classical Class Ib molecules or by non-polymorphic CD1 family of MHC like molecules (CD1c) to gd T cells. In general, gd TCRs lack the fine antigenic specificity of ab TCRs and are often broadly cross reactive. Fig 11.5  gd T cells: Ag recognition and activation The gd T cells respond to a wide variety of bacterial, protozoan & viral molecules & products, including – peptides, – proteins, – pyrophosphates, – phospholipids, – lipoproteins, – phosphorylated oligonucleotides and – alkyl amines. Some gd T cell subsets (defined by V segment usage) are specific to certain type of determinants and thus may counter a whole group of pathogens.  gd T cells: Ag recognition and activation Some gd T cell subsets are specific to stress molecules that are expressed only by host cells suffering from injury, infection or cancerous transformation. Expression of single stress Ag in response to a variety of infections/injuries allows a gd T cell population with limited Ag receptor repertoire to monitor a variety of assaults. Some stress molecules are small pyrophosphate-like molecules, while others are peptides or whole proteins e.g. heat shock proteins (HSPs) released by necrotic cells.  gd T cells: Ag recognition and activation The activation of some gd T cells may be regulated more like that of NK cells than ab T cells as some gd T cells express NK inhibitory receptors that recognize MHC class I. Some gd T cells can be activated with phosphorylated metabolites without CD28 or CD40-mediated costimulation.  gd T cells: Ag recognition and activation The gd T cells in peripheral tissues tend to undergo conventional CD28-mediated costimulation; whereas epidermal & intestinal gd T cells are costimulated when other surface receptors are engaged by stress ligands. In sites of inflammation, APCs may help to activate gd T cells by supplying stimulatory cytokines or unknown intercellular contacts.  gd T cells: Effector functions Once activated by Ag, gd T cells generate effectors in a manner similar to ab T cells, although the signaling pathways linking TCR stimulation to new transcriptions are slightly different.  gd T cells: effector functions Cytokines produced by gd Th effectors activate NK cells and macrophages; support the differentiation of activated ab Th0 cells into conventional ab Th1, Th2 or Th17 effectors and influence isotype switching in B cells. In addition to cytokines, gd T cells secrete molecules that influence leukocyte trafficking and wound healing. Activated gd T cells can induce neighboring epithelial cells to produce the antimicrobial compound nitric oxide (NO).  gd T cells: effector functions In the skin, activated gd T cells secrete keratinocyte growth factor (KGF) that stimulates the growth and differentiation of skin epithelial cells necessary to close wounds. Immunological memory is not a feature of gd T cells. Recent studies also suggest that gd T cells may themselves serve as antigen presenting cells (APCs) to ab T cells.  Development of gd T cells The first waves of T cells produced in human or mice embryo are gd T cells. Rearrangement of TCRgd genes is detected in thymocytes by 8 weeks in human fetus & by day 12.5 of gestation in mice. Under the influence of fetal thymic stromal cells, distinct waves of gd T cells come out to populate specific organs. These gd T cells provide immune defense in fetus and neonates before adaptive immunity mediated by the more powerful ab T cells is fully established.  Development of gd T cells gd T cells arise in thymus from the same NK/T precursor which generates ab T cell & NK cell but it is not known which specific precursor is destined to become gd T cell. Positive & negative thymic selections & peripheral tolerance do occur for gd T cells similar to ab T cells but molecular details are not known.  NKT cells: Overview NKT cells are T lineage cells that have morphological and functional characteristics common to both CTL & NK cells. Low numbers of NKT cells are found virtually everywhere T and NK cells are found: in peripheral blood, spleen, liver, thymus, bone marrow and lymph nodes.  NKT cells: Overview Following their activation, NKT cells can immediately commence cytokine secretion without first to differentiate into effector cells. The rapid response of these makes them important players in the very first line of defense against some bacterial and viral infections. Many of the cytokines produced by NKT cells have powerful effects on ab T cells differentiation and functions, linking NKT cells to adaptive defense.  NKT cells: Ag recognition and activation TCRs of NKT cells recognize glycolipid, glycosphingolipid or lipids presented on non-polymorphic CD1d molecules expressed by professional & non-professional APCs. NKT cell receptors: – In contrast to vast diversity of TCRab sequences, NKT cells carry a ‘semi-variant’ TCRab in which TCRa chain is essentially invariant but TCRb chain is diversified. – Thus, they are also referred as invariant or iNKT cells. – Similar to ab TCR, intracellular signaling in NKT cells is conveyed by CD3 complex. – Human NKT cells are CD4+CD8-, CD4-CD8+ or CD4-CD8-.  NKT cells: Ag recognition and activation NKT cell antigens: – Several pathogen & host derived glycolipids act as NKT antigens. Microbes that contain CD1d-restricted glycolipid Ags which engage TCR of a NKT cell can activate it directly without the need for costimulation or cytokine receptor engagement. Microbes that do not contain such glycolipid Ags can still activate NKT cells via indirect routes. In some cases, despite engagement of its TCR by the host glyolipid-CD1d complex, NKT cell may not be activated unless its IL-12/IL-18 or IFNa/b receptors are engaged.  NKT cells: Activation Fig 11.7.  NKT cells: effector functions Characteristics of NKT cell activation are consistent with those of a cell type prominent in induced innate immunity. NKT cell can immediately carry out their effector functions without the need for differentiation. The most important in vivo effector function of activated NKT cells is cytokine and chemokine secretion. Read details on the figure from the textbook. Fig 11.8: Effector function of NKT cells.  NKT cells: Development NKT cells strictly speaking is a member of the adaptive immune system; however, NKT cells also exhibit characteristics of cells in the innate immune system. NKT cell develop in the thymus from the same NK/T precursors that give rise to ab T and gd T cells. Cells destined to become NKT cells follow the ab T cell developmental pathway until they diverge from them during the DP stage. Once immature NKT cells are positively selected, IL-15 produced by a non-hematopoietic cell type in thymus drives continued NKT maturation.  Next Lecture Chapter 12: Mucosal and Cutaneous immunity.