Spontaneous T Cell Proliferation: A Physiologic Process to Create and Maintain Homeostatic Balance and Diversity of the Immune System

Abstract

Naive T lymphocytes undergo heterogeneous proliferative responses when introduced into lymphopenic hosts, referred to as "homeostatic proliferation" and "spontaneous proliferation." Spontaneous proliferation is a unique process through which the immune system generates memory phenotype cells with increasing T cell receptors repertoire complexity. Here, the mechanisms that initiate and control spontaneous proliferation are discussed.

Keywords: T cells; homeostasis; lymphocytes; lymphopenia; proliferation.

Figure 1

Model for homeostatic and spontaneous proliferation. (A) Quantitative and qualitative signaling model. The model depicts potential signaling mechanisms during homeostatic and spontaneous proliferation. Homeostatic proliferation is triggered by excessive soluble resources available under lymphopenic environments. By contrast, spontaneous proliferation is triggered by different types of signaling mechanism only available under lymphopenic conditions. (B) Relative T cell receptors signal strength against endogenous peptide:MHC complexes determines which T cells undergo homeostatic and spontaneous proliferation. The higher the strength is, the more likely the T cells would undergo spontaneous proliferation. If the strength is below threshold, cytokine availability controls homeostatic proliferation. T cells would remain undivided.

Figure 2

Flowchart for homeostatic and spontaneous proliferation. (A) Homeostatic proliferation. The first step for T cells to check is whether there is sufficient homeostatic factor available. Once the source is available, then the relative affinity of each T cells expresses against MHC-self-antigens (or exogenous antigen as well) will determine proliferation. (B) Spontaneous proliferation. Unlike homeostatic proliferation, the first step deciding spontaneous proliferation is whether there is a memory population in the periphery. The lack of any memory population triggers a full blown spontaneous proliferation during which T cells with higher affinity to MHC-self-antigens (and commensal antigens) are induced for proliferation. If there is a population of pre-existing memory cells, the complexity of T cell receptors (TCR) repertoire will then become the next step determining proliferation. Only incomplete repertoire complexity of memory cells will allow spontaneous proliferation to occur. The final decision will depend upon the TCR that each T cell expresses. Only if the TCR strength toward endogenous peptides (self or commensal) is above threshold, they will be allowed to undergo proliferation.

Figure 3

Memory cell-induced regulation of spontaneous proliferation operates via antigen presenting cells (APCs). Mixed bone marrow chimeras in which different APC populations expressing MHC I and II or MHC I alone (A) or expressing different MHC II haplotypes (B) are created. The first cohort of CD4 T cells is transferred to generate “pre-existing” memory phenotype cells. The second cohort of naive CD8 (A) or naive CD4 (B) cells is transferred into the recipients. The model system uncovers that the interaction between APCs and pre-existing memory phenotype CD4 T cells is essential to limit the proliferation of new naive T cells.