The biology of CD4+ T cells in the blood and central nervous system

Voice, Marie Ann (2015). The biology of CD4+ T cells in the blood and central nervous system. University of Birmingham. Ph.D.

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Abstract

CD4\(^+\) T cells modulate an immune response through the production of effector cytokines. In some circumstances the effector function of CD4\(^+\) T cells is diminished, which may have beneficial (peripheral tolerance) or detrimental (exhaustion, senescence) consequences. Here I characterise a population of CD4\(^+\) cells in human peripheral blood which exhibit complete hyporesponsiveness to in vitro stimulation, as indicated by an absence of CD69 upregulation and the failure to secrete any of thirteen candidate cytokines. These T cells had an effector memory phenotype (CD45RA\(^-\)CCR7\(^-\)\(^/\)\(^+\)CD62L\(^{lo}\)CD27\(^{lo}\)), but their intermediate expression of PD-1 did not suggest a state of exhaustion. Although regulatory T cells (CD25\(^{hi}\)CD127\(^{lo}\)) contributed to the hyporesponsive population it was not predominated by this phenotype. However, the possibility that these hyporesponsive cells represent a non-classical regulatory subset could not be excluded.
CD4\(^+\) T cells can enter the central nervous system (CNS) via the blood cerebrospinal fluid barrier, but their biological activity and recruitment pathways are under-defined. Preliminary studies had suggested that hyporesponsive CD4\(^+\) T cells were enriched in uninflamed human cerebrospinal fluid (CSF). However, this investigation found that CSF and brain-derived CD4\(^+\) T cells readily upregulate CD69 upon activation (mouse, human) and have robust IFNγ responses (rat). This evidence supports a role for CD4\(^+\) T cells in CNS immune surveillance and immunity.
This investigation also showed that the proportion of CCR7\(^+\) and CCR7\(^-\) memory CD4\(^+\) T cells in the CSF was a direct reflection of the distribution in the peripheral blood in both mouse and man. This suggests that CSF recruitment is not CCR7-dependent as is previously described, and shows effector memory cells enter the CSF space in the absence of neuropathology. Such findings have implications for the understanding of normal immune function in the CNS, and the protective or pathogenic contribution of CD4\(^+\) T cells to neuroinflammatory disorders such as multiple sclerosis.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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