T cell immune reconstitution following lymphodepletion

doi:10.1016/j.smim.2007.10.004

Seminars in Immunology

Volume 19, Issue 5, October 2007, Pages 318-330

https://doi.org/10.1016/j.smim.2007.10.004 Get rights and content

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.

Introduction

Reconstitution of T cell dependent immunity is a critical issue for patients treated with lymphodepleting regimens. Chemotherapy or transplant preparative regimens result in a severe and protracted lymphopenia. The recovery of T cell populations is delayed compared to that of myeloid, NK or B cells [1]. Furthermore, T cell function often remains compromised even after normal lymphocyte numbers have recovered [2], [3], [4]. This prolonged period of T cell dysfunction may have serious clinical consequences. It may limit response to vaccines, reduce resistance to infection, permit tumor relapse, and contribute to the development of autoimmunity [3], [4], [5], [6]. Yet at the same time, recent work has suggested that the immediate period of lymphopenia post-cytoreduction provides a unique opportunity for effective anti-tumor immunotherapy [7], [8], [9], [10]. An understanding of the processes of immune reconstitution that underlie this apparent paradox is critical, not only to address the deficits in immune competence, but also to manipulate the process of reconstitution to enhance immune therapy.

T cell immune reconstitution is dependent upon the contributions of two primary pathways: generation of new T cells from progenitors via thymopoiesis, and peripheral expansion of residual mature lymphocytes by antigenic stimulation and homeostatic cytokines [11]. The process of reconstitution involves a dynamic balance between the two pathways. Peripheral expansion pathways affect immediate reconstitution, while thymic dependent pathways may not fully impact on reconstitution for 1–2 years. The cumulative contribution from each pathway may vary depending upon host age, residual T cell subsets, homeostatic cytokine levels and endogenous antigenic stimulation. The sequelae of the two pathways are also quite disparate, resulting in either a diverse T cell repertoire through active thymopoiesis or a skewed, oligoclonal, peripherally derived population. In the years since the two developmental pathways were described, significant progress has been made toward understanding the cellular and cytokine regulators of both renewed thymopoiesis and peripheral expansion. This appreciation of the mechanisms of T cell recovery has, in turn, suggested new strategies to manipulate these processes to improve immune therapy.

Section snippets

Thymic dependent T cell reconstitution: assessment of thymic contribution

The fundamental route for the generation of T cells is thymopoiesis. When peripheral T cell populations are severely depleted, a renewal of thymic activity can contribute to the reconstitution of these peripheral T cell populations by generating naïve T cells de novo. CD4 helper, CD8 cytotoxic effector and CD4+ CD25++ regulatory T cells all mature in the thymus. During thymopoiesis, bone marrow-derived T progenitors traverse to the thymus, become committed to the T lineage, and undergo

Thymic dependent immune reconstitution: determinants and consequences

Although the thymus involutes with age and injury, the thymus has a remarkable capacity for renewal. With active thymopoiesis, young mice and children rapidly recover naïve cells after high dose chemotherapy. In contrast, in thymectomized mice or individuals with inadequate thymopoiesis, naïve cell reconstitution is impaired [13], [14], [16], [19], [20]. In as few as 2 weeks post-transplant in mice, thymic size and cellularity increase and maturing thymocyte subsets reappear [21]. In humans

T Cell reconstitution by homeostatic proliferation

Although the thymic dependent pathway can provide stable, diverse T cell reconstitution, the contributions of this path to immune recovery are delayed by the period of thymic reconstruction. In contrast, mature T cells transferred into lymphopenic hosts immediately begin to proliferate and replenish the T cell compartment [13]. Adoptive transfer of syngeneic bone marrow (BM) cells and congenic lymph node cells to C57BL/6 irradiated, thymus-intact or thymectomized recipients resulted in sharply

IL-7 tightly regulates the naïve T cell compartment in normal states and drives HPE following lymphopenia

IL-7 is a critical, non-redundant cytokine required for stimulating naïve T cell expansion during HPE and sustaining naïve T cell survival. Naïve CD4+ and CD8+ T cells undergo several rounds of CFSE dilution within a week after transfer into irradiated lymphopenic hosts. Naïve T cells adoptively transferred into IL-7^−/− mice not only failed to undergo the HPE observed in wild type (WT) hosts, but also failed to survive [62], [63]. Administration of IL-7 led to a normalization of naïve T cell

IL-15 and TGFβ regulation of memory CD8+ cells influences T cell reconstitution after lymphopenia

Unlike IL-7, IL-15 has little effect on naïve T cells, but is important in the expansion and survival of memory CD8+ T cells. Although memory CD8+ T cells can be generated in IL-15^−/− mice, they do not persist [75], [76]. Administration of IL-15 reversed this phenotype [75]. Bromodeoxyuridine (BRDU) analysis of IL15^−/− and wildtype mice confirmed that IL-15 acts by inducing proliferation of CD8+ T cells [77]. Subsequent studies revealed that IL-15 provides a survival signal as well,

Regulatory T cells constrain CD4+ and CD8+ T cell compartments, influencing the host-reactivity of T cells during immune reconstitution

In addition to the known homeostatic cytokine regulators of CD4+ and CD8+ T cells, peripheral expansion of both populations are influenced by regulatory T cells (Treg). Treg are CD127⁻CD25⁺⁺ CD4⁺ T cells that function to control autoimmune responses [93], [94]. Characterized by the presence of the transcription factor FoxP3, Treg cells can mature in the thymus or can be generated in the periphery from CD25⁻ CD4+ cells [94]. Generation of Treg in the periphery is dependent upon the cytokine

Antigen-driven peripheral expansion independent of cytokine control

Antigen-induced T cell proliferation has long been identified as a key determinant in selective expansion of specific T cells; in 1996, Mackall et al. showed that peripheral expansion of TCR transgenic cells was exponentially increased when the cognate antigen was present [103]. Recently Min and Paul have explored a role for peripheral expansion that occurs independent of cytokines in lymphopenic conditions. Using a murine model, Min et al. demonstrated that adult congenic CD4+ T cells

Peripheral expansion after lymphopenia enhances vaccine and tumor specific T cell responses

The rapid cytokine-fueled, antigen-driven expansion of T cells transferred into a lymphopenic host lends this time frame to vaccine introduction or adoptive transfer of T cells to promote anti-tumor immunity. Several recent studies demonstrate that severe lymphodepletion can create optimal conditions to promote graft versus tumor responses. T cells undergoing peripheral expansion in sublethally irradiated lymphopenic mice developed CD8+ tumor-specific effectors against established tumors [8].

Homeostatic proliferation and thymic insufficiency contribute to GVHD

The mechanisms that may enhance tumor immunity in autologous transplant can contribute to the development of acute and chronic graft versus host disease (GVHD) in the context of allogeneic transplant. Graft versus host disease has been linked to the development of donor anti-host T cells. Since the early post-transplant milieu favors proliferation of T cells within the graft rather than de novo T cell generation through thymopoiesis, alloimmunity can be exacerbated in the acute post-transplant

Conclusion and trends for the future: manipulation of immune reconstitution to enhance anti-tumor effectors and limit immune dysfunction

T cell recovery following lymphopenia is delayed and incompetent compared to other immune cells. This has profound consequences for the individual in terms of anti-tumor and overall immunity. Initial peripheral T cell proliferation, due to the prolific cytokine milieu for HPE and antigen-driven signals, leads to recovery of an oligoclonal, restricted repertoire of T cells. While this predisposes to alloimmunity and impairs clearance of infectious agents, it also permits a maximal expansion of

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ReviewT cell immune reconstitution following lymphodepletion

Abstract

Introduction

Section snippets

Thymic dependent T cell reconstitution: assessment of thymic contribution

Thymic dependent immune reconstitution: determinants and consequences

T Cell reconstitution by homeostatic proliferation

IL-7 tightly regulates the naïve T cell compartment in normal states and drives HPE following lymphopenia

IL-15 and TGFβ regulation of memory CD8+ cells influences T cell reconstitution after lymphopenia

Regulatory T cells constrain CD4+ and CD8+ T cell compartments, influencing the host-reactivity of T cells during immune reconstitution

Antigen-driven peripheral expansion independent of cytokine control

Peripheral expansion after lymphopenia enhances vaccine and tumor specific T cell responses

Homeostatic proliferation and thymic insufficiency contribute to GVHD

Conclusion and trends for the future: manipulation of immune reconstitution to enhance anti-tumor effectors and limit immune dysfunction

Blood

Blood

Blood

Cell

Biol Blood Marrow Transplant

Blood

Lancet

Blood

Biol Blood Marrow Transplant

Blood

Dev Comp Immunol

Immunity

Blood

Blood

Exp Gerontol

Blood

Blood

Blood

Blood

Blood

Growth Horm IGF Res

Blood

Blood

Trends Immunol

Blood

Blood

Blood

Blood

Blood

J Biol Chem

Immunity

Blood

Immunity

Biol Blood Marrow Transplant

Blood

Clin Immunol

Blood

Blood

Biol Blood Marrow Transplant

Humoral immunity to viral and bacterial antigens in lymphoma patients 4–10 years after high-dose therapy with ABMT Serological responses to revaccinations according to EBMT guidelines

Bone Marrow Transplant

Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes

Science

T cell homeostatic proliferation elicits effective antitumor autoimmunity

J Clin Invest

Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells

J Exp Med

Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells

J Clin Invest

Pathways of T-cell regeneration in mice and humans: implications for bone marrow transplantation and immunotherapy

Immunol Rev

Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy

N Engl J Med

Age-dependent incidence, time course, and consequences of thymic renewal in adults

J Clin Invest

Different contributions of thymopoiesis and homeostasis-driven proliferation to the reconstitution of naive and memory T cell compartments

Proc Natl Acad Sci USA

Changes in thymic function with age and during the treatment of HIV infection

Nature

Age-related thymic activity in adults following chemotherapy-induced lymphopenia

Eur J Clin Invest

Review
T cell immune reconstitution following lymphodepletion