The Body’s Defense against Infection Adaptive Immunity Dr. Conrad—April 7, 2009

Objectives To understand the importance of both the innate and adaptive immune system in controlling pathogens To understand the function/role of Th1 versus Th2 versus Th17 To understand the architecture of the secondary lymphoid tissue and the role that various regions play in the adaptive response. To understand why different pathogens require a different adaptive response.

Innate vs Adaptive IR Innate is immediate and lack of innate is quickly fatal Adaptive is slower since specific receptors need to develop Result of no adaptive is still death

Antigen is carried to secondary lymphoid tissues Within Macrophages Within or on Dendritic cells M cells – see figure – specialized cells in gut –tranfer to Peyers patches

Lymphocytes and HEV T (and B) arrive courtesy of HEV Dendritic cells produce cytokine (DC-CK) that attracts naïve T cells Match starts activation process

Filtering of pathogen (antigen) Over 99% of bacteria removed when passed through a LN – trapping by dendritic cells and macs – and antigen specific lymphocytes at later time points.

Th1 vs Th2 (vs Th17) Three extremes in T activation Th1 – cellular Th2 – humoral Th17 – inflammatory Innate immunity cytokines important in initiation of T activation response

Important Innate cytokines -- IL-12 – Dendritic cells and macrophages – stimulates IFN-γ production and Th1 development. IL-4 – stimulates Th2 – cell type that initially makes IL-4?? IL-6 and TGFβ/IL-1 – then get IL-23 and Th17 Antigen load – High usually get Th1 or Th17 Low – Th2 (e.g. allergy)

Initial response to antigen determines whether will be a Th1, Th17 or Th2 response

Results of immune response (success/failure) very dependent on which effector cell is activated

Leprosy example in Humans Highly localized disease correlates with Th1 activation and good prognosis. Dissiminated disease correlates with Th2 and poor prognosis. Potential treatment is with IFN-γ

Role of CTL Complicated – fits with a cellular response but production of IL-10 and TGFβ can suppress Th1 response. May explain lepromatous leprosy – in that the CTL cytokine production inhibits Th1. Possible etiological explanation is that CTL kill viral infected cells, but eventually want Th2 for Ab response and long-lived protection.

Another example – Hemolytic Disease of the Newborn Antibody (Th2) results in fetal hemolysis as a result of placental transfer of IgG anti-RBC. Immediately after birth, mother is given anti-Rh – suppresses the humoral response by an antibody feedback mechanism.

ABO Bloodgroups – mainly IgM

Recent work has shown two other ways that CD4+ T cells can differentiate. Regulatory T cells − Environment rich in TGFβ Associated with transcription factor FOXP3 Patients who lack FOXP3 have increased autoimmunity. Tregs may block tumor immunity – high Treg activity may correlate with increased neoplasia.

IL-23 caused expansion of Th17 cells Named due to high level of the cytokine IL-17 that is produced; IL-22 another cytokine produced by this lineage. The Th17 cell differentiates from naïve CD4+T cells in an environment rich in IL-6 and TGFβ (IL-1 in human)and the newly formed Th17 cells are expanded by IL-23. IL-17 deficient mice show increased susceptibility to Klebsiella pneumoniae (extracellular infection)– indicating Th1 not the entire answer. These same mice – less susceptible to autoimmunity – especially experimental allergic encephalomyelitis (EAE) and arthritis. Experimental induction by blocking IFNγ and IL-4 and adding IL-23, IL-6 and TGFβ.

Both also use a shared receptor chain (IL-12Rβ1) IL-12 and 23 sharing The delay in finding Th17 cell is partly due to the sharing of chains seen between IL-12 and IL-23. Both cytokines use the p40 subunit, but have unique p35 (IL-12) or p19 (IL-23) chains. Both also use a shared receptor chain (IL-12Rβ1) Transciption factor induction is different – explaining the different phenotype.

Environment for Th17 (and Th1 or Th2) induction Induced by IL-6 and TGFβ/IL-1 – when IL-23 receptors are present, IL-23 then causes expansion. Blocked by Th1 or Th2 cytokines

Treg Block Activation of Th1, Th2 or Th17 cells Importance of cytokine environment!

Summary of Th Cell Types and Roles Cancer?

Importance of Adhesion Molecules—Get Effector T cells to Sites of Infection Initial important adhesion molecules are L-selectin and ICAM-1—e.g. HEV

Adhesion molecules … Activated or memory T lose L selectin – get increased expression of VLA4 – VCAM-1 – Induced by inflammatory cytokines Adhesion molecules also play a role in directing effector T to specific anatomical sites – e.g. MAdCAM-1 on gut epithelium interacting with LPAM-1

What happens if adhesion molecules are defective? LADI – integrins are defective LADII – selectins are defective. Patients have severe recurrent infections due to lack of innate immunity.

B cell development to pathogens Importance of Th2 responses B are activated in secondary lymphoid tissue. Arrive through HEV – Interact with Th2 (CD40L)--go into follicles. Some directly differentiate into plasma cells (IgM). Importance of Follicular dendritic cells.

Defective CD40L Hyper IgM symdrome – Class switching is not seen and only IgM is produced Immunity against extracellular pathogens is compromised.

B development … Interaction with FDC – light zone of follicle – FDCs have attached antigen. Somatic mutation occurs – only B cells that have receptors with affinity for antigen survive (affinity maturation). Activated B go to other sites – bone marrow or gut epithelium -- become Plasma cells and produce large amounts of Ab – Germinal centers shut down – primary follicle again. Some of the activated cells become memory B cells.

Picture shows LN or bone marrow IgA (green) or IgG (red) -- LN Lambda or kappa light chains in bottom micrograph (bone marrow smear)

Effector mechanism depends on pathogen

Effector mechanism depends on pathogen

Different pathogens require different T cells for an effective Immune response.

Summary Most infections are highly localized and controlled by innate immune response. If infection (antigen) spreads to secondary lymphoid tissue – then adaptive immune response kicks in. Overall effectiveness depends on the type of T activated – “appropriateness” of the response.