Two sides of a cellular coin: CD4(+)CD3- cells regulate memory responses and lymph-node organization

Abstract

We propose that CD4(+)CD3(-) cells have two functions: a well-established role in organizing lymphoid tissue during development, and a newly discovered role in supporting T-cell help for B cells both during affinity maturation in germinal centres and for memory antibody responses. As CD4(+)CD3(-) cells express the HIV co-receptors CD4 and CXC-chemokine receptor 4, we think that infection of these cells by HIV, and their subsequent destruction by the host immune system, could help to explain the loss of memory antibody responses and the destruction of lymphoid architecture that occur during disease progression to AIDS.

Figure 1. Location of adult CD4⁺CD3⁻CD11c⁻B220⁻ cells

a A digitally processed image of an immunostained section from a mouse spleen is shown, indicating the location of CD4⁺CD3⁻CD11c⁻B220⁻ cells (red) in relation to CD11c⁺ dendritic cells (DCs; green) and IgM⁺ B-cell areas (grey). CD4⁺CD3⁻ cells are mainly located in the region where the T-cell area and the B-cell follicle adjoin (the B–T interface) and adjacent to follicular T cells in B-cell follicles, whereas DCs are located in T-cell areas and the red pulp. Plasma cells are located in the red pulp, which surrounds the white-pulp areas that contain lymphocytes. This image is reproduced with permission from ref. 2 © (2003) Elsevier. b A schematic version of this image is shown.

Figure 2. CD4⁺CD3⁻ cells foster the survival of follicular T cells in germinal centres

a In follicles, follicular T (T_F) cells drive the proliferation of B cells, which then differentiate into centroblasts and undergo somatic hypermutation of their immunoglobulin variable gene segments. The centroblasts proliferate rapidly and differentiate into centrocytes, which compete for antigen fragments that are trapped at the surface of follicular dendritic cells (FDCs). B-cell mutants that have high-affinity B-cell receptors internalize antigen and present peptide fragments to T_F cells, which then provide selective CD40 ligand (CD40L)-dependent rescue signals for B cells. When antigen is scarce, T_F cells are sustained by signalling through OX40 and CD30 that is initiated by CD4⁺CD3⁻ cells, which express OX40 ligand (OX40L) and CD30L constitutively, so that the T_F cells can continue to select B cells. Centrocytes that are positively selected leave the germinal centre (GC) and differentiate into memory B cells or mature into long-lived plasma cells. b Before entry to follicles, antigen-specific T cells (white) are primed by dendritic cells (DCs; green) in the T-cell area (white boxes) of lymph nodes. The T cells then upregulate expression of CXC-chemokine receptor 5 (CXCR5) and migrate into B-cell follicles (white arrow). The red box shows an interaction between a T_F cell and a CD4⁺CD3⁻ cell (red) — which allows signalling through OX40 and CD30 in the T_F cell — in a B-cell-follicle GC, and the panel on the left shows a high-magnification view of this association. This image is reproduced with permission from ref. 2 © (2003) Elsevier. BCR, B-cell receptor; Fc receptor, receptor for immunoglobulin; TCR, T-cell receptor.

Figure 3. CD4⁺CD3⁻ cells foster the survival of memory T cells at the B–T interface

a The mechanism for the re-activation of memory T (T_M) cells by CD4⁺CD3⁻ cells is shown. Antigen- specific T_M cells that co-express CXC-chemokine receptor 5 (CXCR5) and CC-chemokine receptor 7 (CCR7) migrate across high endothelial venules (HEVs) into lymph nodes, owing to the expression of ligands for peripheral-node addressin (PNAD) by these cells. Interleukin-7 (IL-7) that is produced possibly by stromal cells or follicular dendritic cells (FDCs) in lymphoid tissue upregulates the expression of OX40 at the surface of T_M cells. These cells then interact with CD4⁺CD3⁻ cells, which express OX40 ligand (OX40L) constitutively, in the region where the T-cell area and the B-cell follicle adjoin (the B–T interface). The interaction of CD4⁺CD3⁻ cells with T_M cells provides survival signals to T_M cells through OX40, by inducing the upregulation of B-cell lymphoma 2 (BCL-2) and BCL-X_L expression. b An image of the B–T interface is shown. The inset shows a high-magnification view of the interaction of a CD4⁺CD3⁻ cell (red) with a T_M cell (white). This image is reproduced with permission from ref. 2 © (2003) Elsevier.