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The nature of the lymphopenic environment dictates protective function of homeostatic-memory CD8+ T cells.

ABSTRACT: A functional memory T cell pool is critical for resistance to pathogen reinfection. Lymphopenia produces memory-like CD8(+) T cells through homeostatic proliferation, and such "HP-memory" cells can control lethal bacterial infections similarly to conventional, antigen-experienced, memory T cells. These 2 pathways for memory T cell generation are quite distinct. We show here, however, that similar factors are required for production of protective memory CD8 T cells via both homeostatic and conventional pathways. Induction of protective HP-memory CD8 T cells requires CD4(+) T cell "help," which we show is antigen nonspecific yet requires CD40L-CD40 interactions with host cells. The functional competence of HP-memory CD8 T cells also requires release of endogenous bacterial components (which follows irradiation-induced lymphopenia), potentially mimicking the role of adjuvants in conventional immune responses. Lymphopenic environments lacking these key factors support similar CD8 T cell homeostatic proliferation and the acquisition of memory phenotype, yet the HP-memory cells generated are defective in pathogen elimination. These findings suggest unexpected parallels in the requirements for generating protective memory CD8 T cells by distinct pathways, and they suggest ways to bolster immune competence during recovery from lymphopenia.

SUBMITTER: Hamilton SE

PROVIDER: S-EPMC2587628 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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The nature of the lymphopenic environment dictates protective function of homeostatic-memory CD8+ T cells.

Hamilton Sara E SE Jameson Stephen C SC

Proceedings of the National Academy of Sciences of the United States of America 20081119 47

A functional memory T cell pool is critical for resistance to pathogen reinfection. Lymphopenia produces memory-like CD8(+) T cells through homeostatic proliferation, and such "HP-memory" cells can control lethal bacterial infections similarly to conventional, antigen-experienced, memory T cells. These 2 pathways for memory T cell generation are quite distinct. We show here, however, that similar factors are required for production of protective memory CD8 T cells via both homeostatic and conven ...[more]

PMID: 19020089

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Project description:The concept of the brain as an immune privileged organ is rapidly evolving in light of new findings outlining the sophisticated relationship between the central nervous and the immune systems. The role of T cells in brain development and function, as well as modulation of behavior has been demonstrated by an increasing number of studies. Moreover, recent studies have redefined the existence of a brain lymphatic system and the presence of T cells in specific brain structures, such as the meninges and choroid plexus. Nevertheless, much information is needed to further the understanding of brain T cells and their relationship with the central nervous system under non-inflammatory conditions. In the present study we employed the Rag2(-/-) mouse model of lymphocyte deficiency and reconstitution by adoptive transfer to study the temporal and anatomical expansion of T cells in the brain under homeostatic conditions. Lymphopenic Rag2(-/-) mice were reconstituted with 10 million lymphoid cells and studied at one, two and four weeks after transfer. Moreover, lymphoid cells and purified CD4(+) and CD8(+) T cells from transgenic GFP expressing mice were used to define the neuroanatomical localization of transferred cells. T cell numbers were very low in the brain of reconstituted mice up to one week after transfer and significantly increased by 2weeks, reaching wild type values at 4weeks after transfer. CD4(+) T cells were the most abundant lymphocyte subtype found in the brain followed by CD8(+) T cells and lastly B cells. Furthermore, proliferation studies showed that CD4(+) T cells expand more rapidly than CD8(+) T cells. Lymphoid cells localize abundantly in meningeal structures, choroid plexus, and circumventricular organs. Lymphocytes were also found in vascular and perivascular spaces and in the brain parenchyma across several regions of the brain, in particular in structures rich in white matter content. These results provide proof of concept that the brain meningeal system, as well as vascular and perivascular spaces, are homing sites of lymphocytes and suggest the possibility of a brain specific T cell subtype.

Dataset Information

The nature of the lymphopenic environment dictates protective function of homeostatic-memory CD8+ T cells.

Publications

The nature of the lymphopenic environment dictates protective function of homeostatic-memory CD8+ T cells.

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