Page 261 - Clinical Immunology_ Principles and Practice ( PDFDrive )

242 PArT TwO Host Defense Mechanisms and Inflammation

Th1 differentiation by blocking IL-12 production, and enhance maintained at higher frequencies than are naïve cells. Second,
differentiation of T cells toward a Tr1 phenotype. a large portion of memory T cells are maintained in peripheral
tissues, allowing for rapid local responses to infection. Third,
FOLLICULAR HELPER T CELLS (TFH) memory T cells proliferate and produce cytokines in response
to stimulation with lower doses of antigen, less costimulation,
One of the earliest described roles of CD4 T cells is their ability and much faster kinetics compared with naïve T cells. Fourth,
to promote or “help” generate effective antibody production by memory cells enhance can promote APC function and produce
B cells. Th1 and Th2 cells have been described for their ability cytokines that promote the effector differentiation of naïve T cells.
to promote B-cell class switching and effector responses. Evidence Diverse populations of memory T cells can be defined by
supports the role of a distinct subpopulation of T cells, known surface marker expression, localization, and patterns of migration.
as T-follicular helper (Tfh) cells, as playing a key role in regulating Two populations of memory T cells are identified on the basis
T cell–dependent B-cell responses. Tfh cells are identified of their reexpression of the lymph node homing receptors CCR7
by their surface expression of CXCR5, inducible T-cell costimula- and L-selectin following activation. Central memory (T cm ) cells
+
−
+
+
tor (ICOS), programmed death-1 (PD-1), CD200, B- and are identified as CD45RA CD45RO , CCR7 , CD62L , and stem
+
T-lymphocyte attenuator (BTLA), OX40, and serum amyloid P cell memory cells (T scm ) are identified by the markers CD45RA
−
+
+
27
+ 30
(SAP), while lacking the expression of CD127 and CCR7. Tfh CD45RO , CCR7 , CD62L , CD95 . By expressing CCR7 and
cells also express the transcription factor BCL6, which is essential CD62L, these memory T cells permit recirculation through
for their differentiation and function. Interestingly, BCL6 can secondary lymphatic organs, allowing interactions with DCs
be coexpressed with T-bet, GATA3, or RORγt, but BCL6 modifies from diverse tissue sites effectively expanding the area of immune
many of their effector lineage functions. The fact that there is surveillance. T cm and T scm produce IL-2 and rapidly enter the cell
an incomplete separation between Tfh and other T-effector cycle upon activation. T cm and T scm are able to acquire effector
lineages might suggest that the Tfh phenotype is generated in phenotypes, suggesting that they function as a precursor pool
parallel with T-effector cell differentiation and in response to for subsequent immune responses.
inflammatory cues present in lymph nodes. Two additional memory cell subsets have been described on
Tfh differentiation is promoted by signals through ICOS, the basis of their ability to migrate through peripheral tissues.
OX-40, and the presence of IL-6, IL-12, and IL-21. Tfh cells Effector memory T cells (T em ) are identified by the expression
−
−
+
upregulate CXCR5, which enables homing to the interface pattern: CD45RO , CCR7 , CD62L . These cells express chemokine
between the T-cell and B-cell areas of lymph nodes, where they receptors, selectins, and integrins to facilitate their recirculation
interact with recently activated B cells via antigen presentation. through peripheral tissues. T em cells have previously undergone
The B cells provide signals to the Tfh cell through ICOS and effector differentiation, and upon stimulation they rapidly express
IL-6, while the Tfh cells provide CD40L and IL-21 to the B restricted cytokine patterns reflecting their prior phenotype.
cells. Through successive interactions with B cells, Tfh cells Additional populations of nonmigratory memory T cells have
promote the survival, proliferation, Ig class switching, affinity been identified. These are known as tissue resident memory T
+
maturation and differentiation of B cells into memory B cells, cells (T rm ). T rm cells are identified by the markers CD45RO ,
+
−
and antibody-producing plasma cells through the germinal CCR7 , CD69 . They have been identified in close proximity to
center reaction. 28 epithelial sites in multiple tissues. T rm cells provide rapid and
Mutations affecting Tfh-associated pathways have been identi- highly localized cytokine production in response to infection.
fied in B-cell immunodeficiency disorders. Common variable Thus T em and T rm cells bolster immunity by providing immune
immune deficiency (CVID) is often linked to mutations in the surveillance at distinct sites. 31
ICOS pathway. Recurrent infections in patients with CVID are The processes underlying memory T-cell differentiation are
associated with hypogammaglobulinemia and reduced numbers incompletely understood. A number of signaling pathways and
of Tfh cells. X-linked lymphoproliferative disease type 1 (XLP1) APC populations have been proposed to be involved in memory
has been associated with mutations in the SH2D1A gene. Interest- differentiation. It is clear that T cm and T em cells are generated
ingly, patients with XLP1 have defects in B-cell germinal center early in the T-cell response. The pathways that lead to the dif-
formation and decreased memory B-cell numbers but have normal ferentiation of Th1, Th2, Th17, and Tfh effector cells are also
Tfh numbers. XLP1 Tfh cells reduced the ability to support important in the generation of T em populations.
29
B-cell function. Tfh cells have been implicated in autoimmune
diseases, such as myasthenia gravis, Graves disease, Hashimoto GENERAL CONSIDERATIONS IN EFFECTOR
thyroiditis, lupus, Sjögren syndrome, and rheumatoid arthritis, T-CELL DIFFERENTIATION
where dysregulated antibody responses are thought to contribute
to disease progression. In addition, therapies to target or passively Several key concepts of Th maturation should be discussed with
transfer Tfh cells are being studied for treatment of autoimmune regard to the cellular differentiation of CD4 T cells. First and
disease and some forms of lymphoma. 29 foremost, all T-effector, memory, and adaptive Tregs are thought
to arise from naïve thymic emigrant precursors. In addition,
MEMORY T CELLS T-cell phenotype specification is regulated independent of TCR
specificity.
Following an immune response, small numbers of T cells persist Second, differentiation to a specific effector phenotype is
over the long term and are called memory T cells. Memory T cells self-promoting and inhibitory to other phenotypes through
protect the host from reinfection by the same microorganisms. production of effector cytokines (see Fig. 16.3). Early in Th1 or
Protection correlates with the number of specific memory cells Th2 differentiation, for example, expression of the transcription
present in the host. Memory cells accelerate responses against factors T-bet or GATA3, promote proeffector differentiation while
repeat antigen for several reasons. First, memory cells are suppressing alternative cell fates. Once established, T-cell