Since the pioneering work of Gowans and colleagues in the 1960s,1,2 much progress has been made in understanding the pivotal role of cell migration in immunity. We now have considerable knowledge of the way in which specialized leukocytes are channeled to distinct target tissues in immune responses and inflammation (Figure 1). This review will concentrate on the migration of T cells, which are at the heart of most adaptive immune responses. Since T cells respond to pathogens only on direct contact with pathogen-derived antigen, they must migrate to sites where antigen is found. The T-cell receptor recognizes a peptide . . .

T-cell function and migration. Two sides of the same coin.

Objective
A high frequency of infections complicating rheumatoid arthritis (RA) has been described in reports of case series. This retrospective longitudinal cohort study was undertaken to compare the frequency of infections in a population-based incidence cohort of RA patients with that in a group of individuals without RA from the same population.

Methods
RA patients included all members of an incidence cohort of Rochester, Minnesota residents ages ≥18 years who were first diagnosed as having RA between 1955 and 1994. One age- and sex-matched subject without RA was selected for each patient with RA. Study subjects were followed up by review of their entire medical record until death, migration from the area, or study end (January 1, 2000), and details of all documented infections, along with information on potential risk factors for infection, were recorded. Hazard ratios for infections were estimated using stratified Andersen-Gill proportional hazards models, with adjustment for potential confounders.

Results
The 609 RA patients and 609 non-RA study subjects (mean age 58.0 years; 73.1% female) were followed up for a mean of 12.7 years and 15.0 years, respectively, reflecting higher mortality among the group with RA. Hazards ratios for objectively confirmed infections, infections requiring hospitalization, and any documented infection in patients with RA were 1.70 (95% confidence interval [95% CI] 1.42–2.03), 1.83 (95% CI 1.52–2.21), and 1.45 (95% CI 1.29–1.64), respectively, after adjustment for age, sex, smoking status, leukopenia, corticosteroid use, and diabetes mellitus. Sites of infection with the highest risk ratios were bone, joints, skin, soft tissues, and the respiratory tract.

Conclusion
In this study, patients with RA were at increased risk of developing infections compared with non-RA subjects. This may be due to immunomodulatory effects of RA, or to agents with immunosuppressive effects used in its treatment.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.10524

Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study.

Comprehensive assessment of T-cell receptor β-chain diversity in αβ T cells

Generation and maintenance of an effective repertoire of T cell antigen receptors are essential to the immune system, yet the number of distinct T cell receptors (TCRs) expressed by the estimated 10 12 T cells in the human body is not known. In this study, TCR gene amplification and sequencing showed that there are about 10 6 different β chains in the blood, each pairing, on the average, with at least 25 different α chains. In the memory subset, the diversity decreased to 1 × 10 5 to 2 × 10 5 different β chains, each pairing with only a single α chain. Thus, the naive repertoire is highly diverse, whereas the memory compartment, here one-third of the T cell population, contributes less than 1 percent of the total diversity.

https://science.sciencemag.org/content/sci/286/5441/958.full.pdf

A Direct Estimate of the Human αβ T Cell Receptor Diversity

It is now becoming apparent that the immune system undergoes age-associated alterations, which accumulate to produce a progressive deterioration in the ability to respond to infections and to develop immunity after vaccination, both of which are associated with a higher mortality rate in the elderly. Immunosenescence, defined as the changes in the immune system associated with age, has been gathering interest in the scientific and health-care sectors alike. The rise in its recognition is both pertinent and timely given the increasing average age and the corresponding failure to increase healthy life expectancy. This review attempts to highlight the age-dependent defects in the innate and adaptive immune systems. While discussing the mechanisms that contribute to immunosenescence, with emphasis on the extrinsic factors, particular attention will be focused on thymic involution. Finally, we illuminate potential therapies that could be employed to help us live a longer, fuller and healthier life.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2567.2007.02555.x

Immunosenescence: emerging challenges for an ageing population

The ability to mount protective immune responses depends on the diversity of T cells. T cell diversity may be compromised by the declining thymic output of new T cells. The aging process imposes a threat to diversity, because thymic function deteriorates. In this study we have examined the relationship between thymic production, homeostatic T cell proliferation and TCR β-chain diversity in young (∼25 years), middle-aged (∼60 years), and elderly adults (∼75 years). TCR excision circles (TREC) as a marker of thymic output exponentially decreased by >95% between 25 and 60 years of age. The frequency of Ki67 + cycling CD4 T cells remained steady, and surprisingly, the diversity of the naive CD4 T cell repertoire was maintained at ∼2 × 10 7 different TCR β-chains. After the age of 70 years, TRECs only slightly declined, but homeostatic proliferation doubled. The diversity of the T cell pool drastically contracted to 200,000 TCR β-chains. Also, the phenotypic distinction between naive and memory CD4 T cells became fuzzy. The collapse in CD4 T cell diversity during the seventh and eighth decades indicates substantial T cell loss and implies that therapeutic measures to improve vaccine responses will have to include strategies for T cell replenishment.

The Influence of Age on T Cell Generation and TCR Diversity

The immune system is equipped with an extremely large spectrum of structurally diverse receptors to recognize all potential antigens. This fundamental principle of receptor diversity is no longer upheld in patients with rheumatoid arthritis (RA), who have a marked contraction of the T cell receptor repertoire. In this study, the ability of RA patients to produce T cells and to maintain T cell homeostasis was examined. CD4 T cells containing T cell receptor rearrangement excision circles (TREC) were substantially reduced in RA patients; TREC levels in young adult patients matched those of controls 20 years older. Increased self-replication of T cells in RA was indicated by age-inappropriate erosion of telomeres in circulating T cells with almost complete attrition of telomeric reserves in patients 20-30 yr of age. The degree of telomere loss was not related to disease duration or the use of disease-modifying medication and was most pronounced in CD4(+)CD45RO(null) (naive) T cells. The loss of TREC-positive T cells could be a consequence of a primary defect in peripheral T cell homeostasis. Alternatively, RA patients may have impaired thymic function with the increased turnover of peripheral T cells being a secondary compensatory event.

https://www.pnas.org/content/pnas/97/16/9203.full.pdf

T cell homeostasis in patients with rheumatoid arthritis

Aberrations in the T cell repertoire with the emergence of oligoclonal populations have been described in patients with rheumatoid arthritis (RA). However, the extent of the repertoire perturbations as well as the underlying mechanisms are not known. We now have examined the diversity of the peripheral CD4 T cell repertoire by determining the frequencies of arbitrarily selected T cell receptor (TCR) beta-chain sequences. Healthy individuals displayed a highly diverse repertoire, with a median frequency of individual TCR beta-chain sequences of 1 in 2.4 x 10(7) CD4 T cells. In RA patients, the median TCR beta-chain frequency was increased 10-fold, indicating marked contraction of the repertoire (P < 0.001). The loss in TCR diversity was not limited to CD4 memory T cells but also involved the compartment of naive T cells, suggesting that it reflected an abnormality in T cell repertoire formation and not a consequence of antigen recognition in the synovium. Also, control patients with chronic inflammatory disease such as hepatitis C expressed a diverse repertoire indistinguishable from that of normals. Telomere length studies indicated an increased replicative history of peripheral CD4 T cells in RA patients, suggesting an enhanced turnover within the CD4 compartment. Compared with age-matched controls, terminal restriction fragment sizes were 1.7 kilobases shorter (P < 0.001). These data demonstrate an altered CD4 T cell homeostasis in RA that may contribute to the autoimmune response as well as to the immunodeficiency in these patients.

https://www.pnas.org/content/pnas/95/24/14447.full.pdf

Kerstin Koetz

Papers

The Influence of Age on T Cell Generation and TCR Diversity

T cell homeostasis in patients with rheumatoid arthritis

Perturbation of the T cell repertoire in rheumatoid arthritis