Lecture 5 - Adaptive Immunity I

What is adaptive immunity?

-          Clonal expansion: activation and proliferation of lymphocytes already expressing receptors for the specific epitope

-          Receptor diversity: vast repertoire generated by recombination of V(D)J genes

-          Antibody production: class switching, affinity maturation, and secretion of high‑affinity antibodies

-          Antigen specificity: highly discriminating responses targeting unique epitopes

-          Immunological memory: long‑lived memory cells retain information and react quickly and strongly

Explain the main components of the adaptive immune system.

-          Dendritic cells: prepare antigen and present antigen to T and B cells

-          T cells: recognise MHC occupied by antigen via their TCR, instruct other cells by signals (e.g. cytokines)

-          B cells: recognise antigen via their BCR, produce antibody, present antigen

-          Soluble components: Antibody, cytokines and chemokines

How do DCs link to adaptive immunity?

-          DC takes up antigens, leaves the site of infection and enters circulations, then enters the lymph node where it instructs the B- and T-cells by presenting antigens.

Explain the functions of a T-cell.

-          Thymic maturation: Bone‑marrow origin then thymic selection ensures MHC restriction and self‑tolerance

-          Move through different niches where they get positively and engatively selected for so they don’t go against self.

-          TCR specificity — Recognise peptides on MHC complexes via TCR with high level of discrimination (v specific)

-          Major subsets — CD4⁺ helpers, CD8⁺ cytotoxic (go for cells that are expressing a mutated or aberrant self protein). Also Tregs, keep the response in check. Specialised Th lineages

-          Effector roles — Cytotoxicity, cytokine‑driven coordination of immune responses

-          Memory formation — Long‑lived memory cells enable faster, stronger secondary responses

How are T-cells selected for?

-          T-cell precursor rearranges its T-cell receptor genes (VDJ genes) in the thymus

-          Immature T-cells that recognise self MHC receive signals for survival. Those that interact strongly with self-antigen are removed.

-          Mature T0cells encounter foreign antigens in the peripheral lymphoid organs and are activated.

Explain the process of T-cell development

-          When T-cells arrive they don’t expressed the receptors associated with their function (double negative).

-          Move through various zones in the cortex of the lymph-node and they get selected for – may become different types of T-cells.

-          Get to DN3/DN4 where they mature and move into the medulla area, and through interactions with the thymic epithelial cells they begin to express both CD4 and CD8.

-          Interactions with the MTEC test whether reactions occur with the MHCI or MHCII cells, this decides whether it becomes a CD4 or CD8.

-          There are discrete niches the cell shuttles through which results in single positive CD4 or CD8 cells.

-          Want to ensure CD4 cells don’t respond against us.

How is T-cell selection determined by MHCII and peptide recognition>

-          MTEC presents peptides to the T-cell.

-          Looks for a weak recognition of the peptide being accepted.

-          If this reaction is mediated by MHCII, this forms CD4.

-          If its mediated by MHCI, this forms CD8.

-          No recognition by the double positive cell causes it to be classed as anergic and undergoes apoptosis.

-          If they bind tightly to an MTEC then they are deleted.

How is T-cell receptor diversity achieved?

-          V(D)J recombination generates a diverse repertoire of TCR specificities, and thymic selection removes non-functional or strongly self-reactive T-cell clones.

-          Important: V(D)J recombination is random. This creates TCR diversity. But that will include TCRs clones self-reactive to the host or are useless.

-          These are removed or tolerized by thymic selection

-          Signalling through mechanisms such as Notch with thymic epithelial cells induces RAG1/2 (TF) expression in thymic T-cell precursors.

-          This drives V(D)J recombination of TCR genes this generates receptor diversity.

What is a TCR?

-          V(D)J recombination creates the variable region of the TCR, generating a unique antigen-binding site

-          Cone receptors stabilize it an allow for signal transduction.

-          TCRs only recognize peptides, BCRs also recognize sugars.

-          Unlike antibodies, TCRs recognise processed antigen presented by MHC molecules and do not bind free antigen

How do DCs instruct T-cell differentiation and polarisation?

-          Naïve T-cell will be specific to one peptide.

-          TCR-peptide-MHC form tight recognition – crucial for recognition

-          T-cell begins to express genes to produce cytokine.

-          CD28 interaction allows survival.

-          Cytokine secretion and interaction allows differentiation and fine tuning of its response so it can recognise the peptide but also signal to other cells to enhance the immune response.

How does T-cell selection occur?

T-cells migrate rapidly through the lymph-node unless they meet a DC with the right antigen to their TCR, then they stick and divide.

-          Lymph nodes allow small populations of cells to find their host.

What are the phases of the T-cell response?

-          1^st encounter with cognate Ag = T CELL PRIMING =

-          PRIMARY T CELL RESPONSE

-          Activated cell à effector function

-          Memory cells à recall or secondary T-cell response.

How can DCs shape T-cell function?

-          IL-12 and IFNy secretion by DC àTbet and IFNy expression and release: T_H1 (macrophages against bacteria)

-          TIL-4 and7 secretion by DC à GATA-3 expression and IL-4/5/13 secretion by T-cell: T_H2 (eosinophils against helminths)

-          IL-6/23 and TGF0beta secretion by DC à RDRyT expression and Il-17 secretion by T-cell: T_H17 (neutrophils against fungi)

-          IL-10 and TGF-beta secretion by DC à Foxp3 expression and IL10/TGFB secretion by T-cells: iTreg (regulate immunity)

How do cytokines secreted by the CD4 T-cell instruct other immune cells?

-          T_H1 cell and macrophage that’s phagocytosed bacteria.

-          Macrophage can do this without T-cell help, but the T-cell and bind through recognition of peptides that macrophage is presenting.

-          T-cell can secrete cytokines complementary to these receptors, resulting in activation of pathways inside the macrophage which lead to an enhanced immune response.