Spoiling for a Fight: B Lymphocytes As Initiator and Effector Populations within Tertiary Lymphoid Organs in Autoimmunity and Transplantation

Abstract

Tertiary lymphoid organs (TLOs) develop at ectopic sites within chronically inflamed tissues, such as in autoimmunity and rejecting organ allografts. TLOs differ structurally from canonical secondary lymphoid organs (SLOs), in that they lack a mantle zone and are not encapsulated, suggesting that they may provide unique immune function. A notable feature of TLOs is the frequent presence of structures typical of germinal centers (GCs). However, little is known about the role of such GCs, and in particular, it is not clear if the B cell response within is autonomous, or whether it synergizes with concurrent responses in SLOs. This review will discuss ectopic lymphoneogenesis and the role of the B cell in TLO formation and subsequent effector output in the context of autoimmunity and transplantation, with particular focus on the contribution of ectopic GCs to affinity maturation in humoral immune responses and to the potential breakdown of self-tolerance and development of humoral autoimmunity.

Keywords: B cells; autoimmunity; germinal center; tertiary lymphoid organs; transplantation.

Figure 1

Tertiary lymphoid organ (TLO) initiation and formation. (A) TLO-initiating immune cells [among which are lymphoid tissue inducer (LTi)-like cells] accumulate at sites of inflammation and interact with stromal mesenchymal lymphoid tissue organizing (LTo) cells. The binding of LTα₁β₂ on LTi cells with LTβR on LTo cell leads to the release of chemokines CCL19, CCL21, and CXC-chemokine ligand 13 (CXCL13) that mediate further immune cell recruitment and spatial organization within the forming TLO. (B) Similarly, local release of homeostatic chemokines drives the formation of high endothelial venules (HEVs) and lymphangiogenesis, leading to homing of (auto-or alloreactive) naïve and memory B and T cells. A well-organized TLO is composed of compartmentalized T and B cell areas, follicular dendritic cells (FDC), dendritic cells, HEVs, and lymphatic vessels. (C) Under the influence of LTα₁β₂, stromal cells acquire the phenotypic and functional properties of FDCs, which facilitate persistent antigen presentation within TLOs, and CD4⁺ T cells acquire follicular helper (T_FH)-like effector characteristics (CXCR5^hiPD-1^hiICOS^hi) to drive activation of B cells. Cytokines, such as B-cell-activating factor (BAFF), IL-21, and IL-6, contribute to the survival and maintenance of T_FH cells and germinal center (GC) B cells, which subsequently differentiate into antibody-secreting plasma cells.

Figure 2

Potential mechanisms for dysregulated selection within tertiary lymphoid organs (TLOs). A number of mechanisms are responsible for regulating the germinal center (GC) response within conventional secondary lymphoid organs. Affinity maturation is critically dependent upon coordinated recycling through the dark zone, with competition for limiting number of T follicular helper (T_FH) cells critical for selection of high-affinity clones. Effective selection is also dependent upon robust processes for destruction of low-affinity clones or those that have mutated to autoreactivity. These are less well understood, but include: optimization of T_FH cell numbers; negative input from T follicular regulatory (T_FR) cells; and effective engulfment and disposal by tingible body macrophages. In TLOs, dark/light zone segregation is conspicuously absent, and the role of the T_FH cell remains poorly understood. Similarly, the T_FR cell population has yet to be characterized. Thus, although GC-type features are frequently described within TLO, it is likely that functional output of these GC-like structures differs from canonical secondary lymphoid function. We propose that the dysregulated nature of the GC response within TLOs favors the escape of autoreactive variants and developing of long-lasting humoral autoimmunity.