Elsevier

Clinical Immunology

Volume 120, Issue 2, August 2006, Pages 121-128
Clinical Immunology

Short Analytical Review
Autoimmunity during lymphopenia: A two-hit model

https://doi.org/10.1016/j.clim.2006.04.569Get rights and content

Abstract

The immune system has evolved elaborate mechanisms to respond to diverse antigens while minimizing the risk for autoimmune reactivity. During lymphopenia, however, some mechanisms that normally serve to maintain host tolerance are temporarily suspended. Peripheral T cells proliferate in response to self-antigens in lymphopenic hosts, but proliferation toward these same antigens is prevented when T cell numbers are normal. This process, termed homeostatic peripheral expansion, augments peripheral T cell number and limits repertoire skewing during recovery from lymphopenia and also predisposes lymphopenic hosts to autoimmune disease. This paper reviews murine and human settings in which autoimmunity occurs in the context of lymphopenia. We propose a two-hit model, in which lymphopenia plus another insult is sufficient to induce autoimmune disease. Among the secondary insults that appear sufficient to induce autoimmunity during lymphopenia are overproduction of IL-21 as occurs in the NOD.SCID mouse, depletion of Tregs as demonstrated in murine colitis and gastritis models, and tissue inflammation as seen in HIV infected patients who develop immune reconstitution inflammatory syndrome (IRIS). Delineating critical cofactors which result in autoimmune disease during lymphopenia can provide insight into the pathophysiology of naturally occurring autoimmune diseases as well as generating testable hypothesis for inducing tumor-specific autoimmunity in lymphopenic hosts with cancer.

Introduction

The ongoing development of T-cell-based immunotherapy for cancer has focused primarily on vaccines to boost the immune system's ability to recognize tumors as foreign and on adoptive cellular therapy to provide large numbers of tumor-specific effectors. Significant progress has been made in both arenas and promising early clinical results have been reported, but immunotherapy for cancer has not yet had a major impact on this devastating disease [1]. A major issue that continues to limit the effectiveness of T-cell-based immunotherapy for cancer is the difficulty in overcoming tolerance to self-tissues, which tumors represent. To address this, tumor immunotherapists have recently turned to studies of lymphopenia and autoimmunity to identify clues regarding the critical factors necessary to break self-tolerance.

Mechanistic studies, animal models, and clinical experience have demonstrated that alterations in T cell homeostasis induced by lymphopenia are permissive for the breaking of self-tolerance. At the same time, because most lymphopenic hosts do not develop autoimmune disease, important cofactors must also be required to break self-tolerance, even in the setting of lymphopenia. Clues to the nature of the cofactors required for lymphopenia-associated autoimmunity can be gleaned from murine models and clinical studies wherein autoimmune diseases occur in lymphopenic hosts. In this report, we will briefly review the basic biology of lymphopenia as it relates to self-tolerance, then discuss in detail the murine and human settings wherein autoimmune disease occurs in the context of lymphopenia. Our goal is to identify critical common elements among lymphopenia/autoimmunity syndromes, which could guide the development of testable hypotheses for inducing cancer-specific autoimmunity in lymphopenic humans.

Section snippets

T cell homeostasis, lymphopenia, and homeostatic peripheral expansion

Peripheral T cell expansion plays a central role in both T cell maintenance and regeneration. Primary T cell development occurs largely via thymopoiesis but efficient seeding of the neonatal peripheral T cell pool requires post-thymic expansion [2]. Further, because thymic involution occurs early in life, maintenance of the peripheral T cell pool occurs primarily via thymic-independent pathways, and when T cell depletion occurs postnatally, thymic regenerative capacity is limited [3]. Recent

Implications, applications, and conclusions

Together, the mouse and human data demonstrate that although there is a substantial interface between lymphopenia and autoimmunity, the two entities can exist independently from one another. Further, when autoimmunity is associated with lymphopenia, the T cell depletion plays a predisposing role, but it is insufficient to fully explain the loss of self-tolerance. Instead, multiple cofactors appear capable of inducing a loss of self-tolerance during lymphopenia (Fig. 1). We hypothesize that

Acknowledgments

The authors are supported by the Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, Center for Cancer Research. Tom Krupica Jr. is also supported by the HHMI-NIH Research Scholars Program.

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