T cell immune reconstitution following lymphodepletion

Abstract

T cell reconstitution following lymphopenia from chemotherapy or stem cell transplant is often slow and incompetent, contributing to the development of infectious diseases, relapse, and graft-versus-host disease. This is due to the fact that de novo T cell production is impaired following cytoreductive regimens. T cells can be generated from two pathways: (1) thymus derived through active thymopoiesis and (2) peripherally expanded clones through homeostatic proliferation. During recovery from lymphopenia, the thymic pathway is commonly compromised in adults and T cells rely upon peripheral expansion to restore T cell numbers. This homeostatic proliferation exploits the high cytokine levels following lymphopenia to rapidly generate T cells in the periphery. Moreover, this early peripheral expansion of T cells can also be driven by exogenous antigen. This results in loss of T cell repertoire diversity and may predispose to auto- or allo-immunity. Alternatively, the high homeostatic proliferation following lymphopenia may facilitate expansion of anti-tumor immunity. Murine and human studies have provided insight into the cytokine and cellular regulators of these two pathways of T cell generation and the disparate portraits of T cell immunity created through robust thymopoiesis or peripheral expansion following lymphopenia. This insight has permitted the manipulation of the immune system to maximize anti-tumor immunity through lymphopenia and led to an appreciation of mechanisms that underlie graft versus host disease.

Figure 1

Diagrammatic representation of the consequences of robust versus impaired thymopoiesis. In young individuals without GVHD, thymic renewal rapidly ensues following transplant induced lymphopenia, with an increase in thymic size and a subsequent increase in thymic emigrants. The naïve pool is thus enlarged and enriched for newly derived thymic T cells and displays a diverse T cell repertoire, shown diagrammatically as multi-colored cells. In contrast, when thymopoiesis is impaired by age or GVHD, the thymus remains small and releases few new naïve T cells to the peripheral pool during immune reconstitution. The memory pool is expanded and there is less diversity within both the naïve and memory pool.

Figure 2

Diagrammatic representation of homeostatic cycling versus homeostatic peripheral expansion. In normal steady state homeostatic cycling, constitutive IL-7 production provides a survival signal to a diverse array of naïve T cells and maintains a low level of proliferation. Memory CD8+ compartment is similarly regulated by IL-15 production, IL-21 production, and the influence of TGFβ and Treg cells. The influence of these competing factors leads to a smaller and more diverse memory population. In contrast, following depletion of lymphocytes, residual mature T cells rapidly proliferate in response to homeostatic cytokines and antigenic stimulation by homeostatic peripheral expansion. Residual naive cells expand in response to the elevated levels IL-7. Antigen-driven stimulation results in a rapid activation of naïve cells and expansion of memory cells. Furthermore, elevated levels of IL-15, and possibly IL-21, contribute to an early increase in CD8+ memory T cells. Since there are low levels of Treg cells circulating, there is little regulation of this expansion by these cells. This results in a skewed naïve and memory T cell repertoires.

Figure 3

Diagrammatic representation of the timeline of immune reconstitution in a 40 year old CMV seropositive adult. Following cytoreductive therapy, the peripheral CD4 and CD8 T cell populations are severely depleted. The thymus is reduced to a small remnant (shown at 1.5 month post-transplant). CD4 and CD8 T cells immediately undergo a marked expansion in response to homeostatic cytokines and endogenous antigens, generating a population that is mainly composed of memory (green) and effector (orange) T cells, with few naïve (blue) or TREC-bearing cells (also represented at 1.5 month post-transplant). The CD4:CD8 ratio becomes inverted by the more rapid expansion of CD8+ T cells, demonstrated by the peak of (orange) effector CD8 cells as compared to the smaller (green) peak of CD4+ cells at 1.5 months. TCR repertoire diversity, that has been lost by lymphodepletion, is further skewed by oligoclonal expansion of the limited number of remaining cells. The expanded population of CD8 T cells persists and may continue to dominate the CD8 TCR repertoire as shown in subsequent months by the large effector (orange) CD8 population. Renewed thymopoiesis begins within the first 6 months, but the full contribution of naïve, TREC-bearing T cells with a diverse TCR repertoire may require 1 - 2 years to be evident.